Heteroaryl Substituted Pyrrolo[2,3-B] Pyridines And Pyrrolo[2,3-B] Pyrimidines  As Janus Kinase Inhibitors

ABSTRACT

The present invention provides heteroaryl substituted pyrrolo[2,3-b]pyridines and heteroaryl substituted pyrrolo[2,3-b]pyrimidines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 15/173,057, filedJun. 3, 2016, which is a continuation of U.S. Ser. No. 14/711,576, filedMay 13, 2015, which is a continuation of U.S. Ser. No. 14/274,948, filedMay 12, 2014, now U.S. Pat. No. 9,079,912, which is a continuation ofU.S. Ser. No. 14/020,505, filed Sep. 6, 2013, now U.S. Pat. No.9,206,187, which is a divisional of U.S. Ser. No. 13/076,220, filed Mar.30, 2011, now U.S. Pat. No. 8,530,485, which is a continuation of U.S.Ser. No. 12/549,170, filed Aug. 27, 2009, now U.S. Pat. No. 8,541,425,which is a continuation of U.S. Ser. No. 11/637,545, filed Dec. 12,2006, now U.S. Pat. No. 7,598,257, which claims the benefit of U.S. Ser.Nos. 60/749,905, filed Dec. 13, 2005; 60/810,231, filed Jun. 2, 2006;60/850,625, filed Oct. 10, 2006; 60/856,872, filed Nov. 3, 2006; and60/859,404, filed Nov. 16, 2006, the disclosures of each of which areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention provides heteroaryl substitutedpyrrolo[2,3-b]pyridines and heteroaryl substitutedpyrrolo[2,3-b]pyrimidines that modulate the activity of Janus kinasesand are useful in the treatment of diseases related to activity of Januskinases including, for example, immune-related diseases, skin disorders,myeloid proliferative disorders, cancer, and other diseases.

BACKGROUND OF THE INVENTION

Protein kinases (PKs) are a group of enzymes that regulate diverse,important biological processes including cell growth, survival anddifferentiation, organ formation and morphogenesis, neovascularization,tissue repair and regeneration, among others. Protein kinases exerttheir physiological functions through catalyzing the phosphorylation ofproteins (or substrates) and thereby modulating the cellular activitiesof the substrates in various biological contexts. In addition to thefunctions in normal tissues/organs, many protein kinases also play morespecialized roles in a host of human diseases including cancer. A subsetof protein kinases (also referred to as oncogenic protein kinases), whendysregulated, can cause tumor formation and growth, and furthercontribute to tumor maintenance and progression (Blume-Jensen P et al,Nature 2001, 411(6835):355-365). Thus far, oncogenic protein kinasesrepresent one of the largest and most attractive groups of proteintargets for cancer intervention and drug development.

Protein kinases can be categorized as receptor type and non-receptortype. Receptor tyrosine kinases (RTKs) have an extracellular portion, atransmembrane domain, and an intracellular portion, while non-receptortyrosine kinases are entirely intracellular. RTK mediated signaltransduction is typically initiated by extracellular interaction with aspecific growth factor (ligand), typically followed by receptordimerization, stimulation of the intrinsic protein tyrosine kinaseactivity, and receptor transphosphorylation. Binding sites are therebycreated for intracellular signal transduction molecules and lead to theformation of complexes with a spectrum of cytoplasmic signalingmolecules that facilitate the appropriate cellular response such as celldivision, differentiation, metabolic effects, and changes in theextracellular microenvironment

At present, at least nineteen (19) distinct RTK subfamilies have beenidentified. One RTK subfamily, designated the HER subfamily, includesEGFR, HER2, HER3 and HER4, and bind such ligands as epithelial growthfactor (EGF), TGF-α, amphiregulin, HB-EGF, betacellulin and heregulin. Asecond family of RTKs, designated the insulin subfamily, includes theINS-R, the IGF-1R and the IR-R. A third family, the “PDGF” subfamily,includes the PDGF alpha and beta receptors, CSFIR, c-kit and FLK-II.Another subfamily of RTKs, referred to as the FLK subfamily, encompassesthe Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-1), thefetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1 (flt-1).Two other subfamilies of RTKs have been designated as the FGF receptorfamily (FGFR1, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-Met, Ronand Sea). For a detailed discussion of protein kinases, see for example,Blume-Jensen, P. et al., Nature. 2001, 411(6835):355-365, and Manning,G. et al., Science. 2002, 298(5600):1912-1934.

The non-receptor type of tyrosine kinases is also composed of numeroussubfamilies, including Src, Btk, Abl, Fak, and Jak. Each of thesesubfamilies can be further subdivided into multiple members that havebeen frequently linked to oncogenesis. The Src family, for example, isthe largest and includes Src, Fyn, Lck and Fgr among others. For adetailed discussion of these kinases, see Bolen J B. Nonreceptortyrosine protein kinases. Oncogene. 1993, 8(8):2025-31.

A significant number of tyrosine kinases (both receptor and nonreceptor)are associated with cancer (see Madhusudan S, Ganesan T S. Tyrosinekinase inhibitors in cancer therapy. Clin Biochem. 2004, 37(7):618-35.).Clinical studies suggest that overexpression or dysregulation oftyrosine kinases may also be of prognostic value. For example, membersof the HER family of RTKs have been associated with poor prognosis inbreast, colorectal, head and neck and lung cancer. Mutation of c-Kittyrosine kinase is associated with decreased survival ingastrointestinal stromal tumors. In acute myelogenous leukemia, Flt-3mutation predicts shorter disease free survival. VEGFR expression, whichis important for tumor angiogenesis, is associated with a lower survivalrate in lung cancer. Tie-1 kinase expression inversely correlates withsurvival in gastric cancer. BCR-Abl expression is an important predictorof response in chronic myelogenous leukemia and Src tyrosine kinase isan indicator of poor prognosis in all stages of colorectal cancer.

The immune system responds to injury and threats from pathogens.Cytokines are low-molecular weight polypeptides or glycoproteins thatstimulate biological responses in virtually all cell types. For example,cytokines regulate many of the pathways involved in the hostinflammatory response to sepsis. Cytokines influence celldifferentiation, proliferation and activation, and they can modulateboth proinflammatory and anti-inflammatory responses to allow the hostto react appropriately to pathogens.

Binding of a cytokine to its cell surface receptor initiatesintracellular signaling cascades that transduce the extracellular signalto the nucleus, ultimately leading to changes in gene expression. Thepathway involving the Janus kinase family of protein tyrosine kinases(JAKs) and Signal Transducers and Activators of Transcription (STATs) isengaged in the signaling of a wide range of cytokines. Generally,cytokine receptors do not have intrinsic tyrosine kinase activity, andthus require receptor-associated kinases to propagate a phosphorylationcascade. JAKs fulfill this function. Cytokines bind to their receptors,causing receptor dimerization, and this enables JAKs to phosphorylateeach other as well as specific tyrosine motifs within the cytokinereceptors. STATs that recognize these phosphotyrosine motifs arerecruited to the receptor, and are then themselves activated by aJAK-dependent tyrosine phosphorylation event. Upon activation, STATsdissociate from the receptors, dimerize, and translocate to the nucleusto bind to specific DNA sites and alter transcription (Scott, M. J., C.J. Godshall, et al. (2002). “Jaks, STATs, Cytokines, and Sepsis.” ClinDiagn Lab Immunol 9(6): 1153-9).

The JAK family plays a role in the cytokine-dependent regulation ofproliferation and function of cells involved in immune response.Currently, there are four known mammalian JAK family members: JAK1 (alsoknown as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3(also known as Janus kinase, leukocyte; JAKL; L-JAK and Janus kinase-3)and TYK2 (also known as protein-tyrosine kinase 2). The JAK proteinsrange in size from 120 to 140 kDa and comprise seven conserved JAKhomology (JH) domains; one of these is a functional catalytic kinasedomain, and another is a pseudokinase domain potentially serving aregulatory function and/or serving as a docking site for STATs (Scott,Godshall et al. 2002, supra).

While JAK1, JAK2 and TYK2 are ubiquitously expressed, JAK3 is reportedto be preferentially expressed in natural killer (NK) cells and notresting T cells, suggesting a role in lymphoid activation (Kawamura, M.,D. W. McVicar, et al. (1994). “Molecular cloning of L-JAK, a Janusfamily protein-tyrosine kinase expressed in natural killer cells andactivated leukocytes.” Proc Natl Acad Sci USA 91(14): 6374-8).

Not only do the cytokine-stimulated immune and inflammatory responsescontribute to normal host defense, they also play roles in thepathogenesis of diseases: pathologies such as severe combinedimmunodeficiency (SCID) arise from hypoactivity and suppression of theimmune system, and a hyperactive or inappropriate immune/inflammatoryresponse contributes to the pathology of autoimmune diseases such asrheumatoid and psoriatic arthritis, asthma and systemic lupuserythematosus, inflammatory bowel disease, multiple sclerosis, type Idiabetes mellitus, myasthenia gravis, thyroiditis, immunoglobulinnephropathies, myocarditis as well as illnesses such as scleroderma andosteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000). “Janus kinasesand signal transducers and activators of transcription: their roles incytokine signaling, development and immunoregulation.” Arthritis Res2(1): 16-32). Furthermore, syndromes with a mixed presentation ofautoimmune and immunodeficiency disease are quite common (Candotti, F.,L. Notarangelo, et al. (2002). “Molecular aspects of primaryimmunodeficiencies: lessons from cytokine and other signaling pathways.”J Clin Invest 109(10): 1261-9). Thus, therapeutic agents are typicallyaimed at augmentation or suppression of the immune and inflammatorypathways, accordingly.

Deficiencies in expression of JAK family members are associated withdisease states. Jak1−/− mice are runted at birth, fail to nurse, and dieperinatally (Rodig, S. J., M. A. Meraz, et al. (1998). “Disruption ofthe Jak1 gene demonstrates obligatory and nonredundant roles of the Jaksin cytokine-induced biologic responses.” Cell 93(3): 373-83). Jak2−/−mouse embryos are anemic and die around day 12.5 postcoitum due to theabsence of definitive erythropoiesis. JAK2-deficient fibroblasts do notrespond to IFN gamma, although responses to IFNalpha/beta and IL-6 areunaffected. JAK2 functions in signal transduction of a specific group ofcytokine receptors required in definitive erythropoiesis (Neubauer, H.,A. Cumano, et al. (1998). Cell 93(3): 397-409; Parganas, E., D. Wang, etal. (1998). Cell 93(3): 385-95.). JAK3 appears to play a role in normaldevelopment and function of B and T lymphocytes. Mutations of JAK3 arereported to be responsible for autosomal recessive severe combinedimmunodeficiency (SCID) in humans (Candotti, F., S. A. Oakes, et al.(1997). “Structural and functional basis for JAK3-deficient severecombined immunodeficiency.” Blood 90(10): 3996-4003).

The JAK/STAT pathway, and in particular all four members of the JAKfamily, are believed to play a role in the pathogenesis of the asthmaticresponse, chronic obstructive pulmonary disease, bronchitis, and otherrelated inflammatory diseases of the lower respiratory tract. Forinstance, the inappropriate immune responses that characterize asthmaare orchestrated by a subset of CD4+ T helper cells termed T helper 2(Th2) cells. Signaling through the cytokine receptor IL-4 stimulatesJAK1 and JAK3 to activate STAT6, and signaling through IL-12 stimulatesactivation of JAK2 and TYK2, and subsequent phosphorylation of STAT4.STAT4 and STAT6 control multiple aspects of CD4+ T helper celldifferentiation (Pernis, A. B. and P. B. Rothman (2002). “JAK-STATsignaling in asthma.” J Clin Invest 109(10): 1279-83). Furthermore,TYK2-deficient mice were found to have enhanced Th2 cell-mediatedallergic airway inflammation (Seto, Y., H. Nakajima, et al. (2003).“Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficientmice.” J Immunol 170(2): 1077-83). Moreover, multiple cytokines thatsignal through JAK kinases have been linked to inflammatory diseases orconditions of the upper respiratory tract such as those affecting thenose and sinuses (e.g. rhinitis, sinusitis) whether classically allergicreactions or not.

The JAK/STAT pathway has also been implicated to play a role ininflammatory diseases/conditions of the eye including, but not limitedto, iritis, uveitis, scleritis, conjunctivitis, as well as chronicallergic responses. Therefore, inhibition of JAK kinases may have abeneficial role in the therapeutic treatment of these diseases.

The JAK/STAT pathway, and in particular, JAK3, also plays a role incancers of the immune system. In adult T cell leukemia/lymphoma (ATLL),human CD4+ T cells acquire a transformed phenotype, an event thatcorrelates with acquisition of constitutive phosphorylation of JAKs andSTATs. Furthermore, an association between JAK3 and STAT-1, STAT-3, andSTAT-5 activation and cell-cycle progression was demonstrated by bothpropidium iodide staining and bromodeoxyuridine incorporation in cellsof four ATLL patients tested. These results imply that JAK/STATactivation is associated with replication of leukemic cells and thattherapeutic approaches aimed at JAK/STAT inhibition may be considered tohalt neoplastic growth (Takemoto, S., J. C. Mulloy, et al. (1997).“Proliferation of adult T cell leukemia/lymphoma cells is associatedwith the constitutive activation of JAK/STAT proteins.” Proc Natl AcadSci USA 94(25): 13897-902).

Blocking signal transduction at the level of the JAK kinases holdspromise for developing treatments for human cancers. Cytokines of theinterleukin 6 (IL-6) family, which activate the signal transducer gp130,are major survival and growth factors for human multiple myeloma (MM)cells. The signal transduction of gp130 is believed to involve JAK1,JAK2 and Tyk2 and the downstream effectors STAT3 and themitogen-activated protein kinase (MAPK) pathways. In IL-6-dependent MMcell lines treated with the JAK2 inhibitor tyrphostin AG490, JAK2 kinaseactivity and ERK2 and STAT3 phosphorylation were inhibited. Furthermore,cell proliferation was suppressed and apoptosis was induced (De Vos, J.,M. Jourdan, et al. (2000). “JAK2 tyrosine kinase inhibitor tyrphostinAG490 downregulates the mitogen-activated protein kinase (MAPK) andsignal transducer and activator of transcription (STAT) pathways andinduces apoptosis in myeloma cells.” Br J Haematol 109(4): 823-8).However, in some cases, AG490 can induce dormancy of tumor cells andactually then protect them from death.

Activation of JAK/STAT in cancers may occur by multiple mechanismsincluding cytokine stimulation (e.g. IL-6 or GM-CSF) or by a reductionin the endogenous suppressors of JAK signaling such as SOCS (suppressoror cytokine signaling) or PIAS (protein inhibitor of activated STAT)(Boudny, V., and Kovarik, J., Neoplasm. 49:349-355, 2002). Importantly,activation of STAT signaling, as well as other pathways downstream ofJAKs (e.g. Akt), has been correlated with poor prognosis in many cancertypes (Bowman, T., et al. Oncogene 19:2474-2488, 2000). Moreover,elevated levels of circulating cytokines that signal through JAK/STATmay adversely impact patient health as they are thought to play a causalrole in cachexia and/or chronic fatigue. As such, JAK inhibition may betherapeutic for the treatment of cancer patients for reasons that extendbeyond potential anti-tumor activity. The cachexia indication may gainfurther mechanistic support with realization that the satiety factorleptin signals through JAKs.

Pharmacological targeting of Janus kinase 3 (JAK3) has been employedsuccessfully to control allograft rejection and graft versus hostdisease (GVHD). In addition to its involvement in signaling of cytokinereceptors, JAK3 is also engaged in the CD40 signaling pathway ofperipheral blood monocytes. During CD40-induced maturation of myeloiddendritic cells (DCs), JAK3 activity is induced, and increases incostimulatory molecule expression, IL-12 production, and potentallogeneic stimulatory capacity are observed. A rationally designed JAK3inhibitor WHI-P-154 prevented these effects arresting the DCs at animmature level, suggesting that immunosuppressive therapies targetingthe tyrosine kinase JAK3 may also affect the function of myeloid cells(Saemann, M. D., C. Diakos, et al. (2003). “Prevention of CD40-triggereddendritic cell maturation and induction of T-cell hyporeactivity bytargeting of Janus kinase 3.” Am J Transplant 3(11): 1341-9). In themouse model system, JAK3 was also shown to be an important moleculartarget for treatment of autoimmune insulin-dependent (type 1) diabetesmellitus. The rationally designed JAK3 inhibitor JANEX-1 exhibitedpotent immunomodulatory activity and delayed the onset of diabetes inthe NOD mouse model of autoimmune type 1 diabetes (Cetkovic-Cvrlje, M.,A. L. Dragt, et al. (2003). “Targeting JAK3 with JANEX-1 for preventionof autoimmune type 1 diabetes in NOD mice.” Clin Immunol 106(3):213-25).

It has been suggested that inhibition of JAK2 tyrosine kinase can bebeneficial for patients with myeloproliferative disorder. (Levin, etal., Cancer Cell, vol. 7, 2005: 387-397) Myeloproliferative disorder(MPD) includes polycythemia vera (PV), essential thrombocythemia (ET),myeloid metaplasia with myelofibrosis (MMM), chronic myelogenousleukemia (CML), chronic myelomonocytic leukemia (CMML),hypereosinophilic syndrome (HES) and systemic mast cell disease (SMCD).Although the myeloproliferative disorder (such as PV, ET and MMM) arethought to be caused by acquired somatic mutation in hematopoieticprogenitors, the genetic basis for these diseases has not been known.However, it has been reported that hematopoietic cells from a majorityof patients with PV and a significant number of patients with ET and MMMpossess a recurrent somatic activating mutation in the JAK2 tyrosinekinase. It has also been reported that inhibition of the JAK2V617Fkinase with a small molecule inhibitor leads to inhibition ofproliferation of hematopoietic cells, suggesting that the JAK2 tyrosinekinase is a potential target for pharmacologic inhibition in patientswith PV, ET and MMM.

Inhibition of the JAK kinases is also envisioned to have therapeuticbenefits in patients suffering from skin immune disorders such aspsoriasis, and skin sensitization. In psoriasis vulgaris, the mostcommon form of psoriasis, it has been generally accepted that activatedT lymphocytes are important for the maintenance of the disease and itsassociated psoriatic plaques (Gottlieb, A. B., et al, Nat Rev DrugDisc., 4:19-34). Psoriatic plaques contain a significant immuneinfiltrate, including leukocytes and monocytes, as well as multipleepidermal layers with increased keratinocyte proliferation. While theinitial activation of immune cells in psoriasis occurs by an ill definedmechanism, the maintenance is believed to be dependent on a number ofinflammatory cytokines, in addition to various chemokines and growthfactors (JCI, 113:1664-1675). Many of these, including interleukins-2,-4, -6, -7, -12, -15, -18, and -23 as well as GM-CSF and IFNg, signalthrough the Janus (JAK) kinases (Adv Pharmacol. 2000; 47:113-74). Assuch, blocking signal transduction at the level of JAK kinases mayresult in therapeutic benefits in patients suffering from psoriasis orother immune disorders of the skin.

It has been known that certain therapeutics can cause immune reactionssuch as skin rash or diarrhea in some patients. For instance,administration of some of the new targeted anti-cancer agents such asIressa, Erbitux, and Tarceva has induced acneiform rash with somepatients. Another example is that some therapeutics used topicallyinduce skin irritation, skin rash, contact dermatitis or allergiccontact sensitization. For some patients, these immune reactions may bebothersome, but for others, the immune reactions such as rash ordiarrhea may result in inability to continue the treatment. Although thedriving force behind these immune reactions has not been elucidatedcompletely at the present time, these immune reactions are likely linkedto immune infiltrate.

Inhibitors of Janus kinases or related kinases are widely sought andseveral publications report effective classes of compounds. For example,certain inhibitors are reported in WO 99/65909, US 2004/0198737; WO2004/099204; WO 2004/099205; and WO 01/42246. Heteroaryl substitutedpyrroles and other compounds are reported in WO 2004/72063 and WO99/62908.

Thus, new or improved agents which inhibit kinases such as Janus kinasesare continually needed that act as immunosuppressive agents for organtransplants, as well as agents for the prevention and treatment ofautoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis,asthma, type I diabetes, inflammatory bowel disease, Crohn's disease,autoimmune thyroid disorders, Alzheimer's disease), diseases involving ahyperactive inflammatory response (e.g., eczema), allergies, cancer(e.g., prostate, leukemia, multiple myeloma), and some immune reactions(e.g., skin rash or contact dermatitis or diarrhea) caused by othertherapeutics, to name a few. The compounds, compositions and methodsdescribed herein are directed toward these needs and other ends.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I:

or pharmaceutically acceptable salt forms or prodrugs thereof, whereinconstituent members are defined herein.

The present invention further provides compositions comprising acompound of Formula I, or pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.

The present invention further provides methods of modulating an activityof JAK comprising contacting JAK with a compound of Formula I, orpharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease ina patient, wherein the disease is associated with JAK activity,comprising administering to the patient a therapeutically effectiveamount of a compound of Formula I, or pharmaceutically acceptable saltthereof.

DETAILED DESCRIPTION

The present invention provides, inter alia, compounds that modulate theactivity of one or more JAKs and are useful, for example, in thetreatment of diseases associated with JAK expression or activity. Thecompounds of the invention have Formula I:

including pharmaceutically acceptable salt forms or prodrugs thereof,wherein:

A¹ and A² are independently selected from C and N;

T, U, and V are independently selected from O, S, N, CR⁵, and NR⁶;

wherein the 5-membered ring formed by A¹, A², U, T, and V is aromatic;

X is N or CR⁴;

Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene,(CR¹¹R¹²)_(p)—(C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(arylene)-(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)—(C₁₋₁₀heterocycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(heteroarylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)S(CR¹¹R¹²)_(q),(CR¹¹R¹²)C(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)OC(O)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)OC(O)NR^(c)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)NR^(c)C(O)NR^(d)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)S(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)S(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)S(O)₂(CR¹¹R¹²)_(q), or (CR¹¹R¹²)_(p)S(O)₂NR(CR¹¹R¹²)_(q),wherein said C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene,cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, isoptionally substituted with 1, 2, or 3 substituents independentlyselected from -D¹-D²-D³-D⁴;

Z is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, ═C—R^(i), ═N—R^(i),Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl)R^(b), andS(O)₂NR^(c)R^(d), wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl))R^(b), andS(O)₂NR^(c)R^(d);

wherein when Z is H, n is 1;

or the —(Y)_(n)—Z moiety is taken together with i) A² to which themoiety is attached, ii) R⁵ or R⁶ of either T or V, and iii) the C or Natom to which the R⁵ or R⁶ of either T or V is attached to form a 4- to20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fusedto the 5-membered ring formed by A¹, A², U, T, and V, wherein said 4- to20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring isoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from —(W)_(m)-Q;

W is C₁₋₈ alkylenyl, C₂₋₈ alkenylenyl, C₂₋₈ alkynylenyl, O, S, C(O),C(O)NR^(c′), C(O)O, OC(O), OC(O)NR^(c′), NR^(c′), NR^(c′)C(O)NR^(d′),S(O), S(O)NR^(c′), S(O)₂, or S(O)₂NR^(c′); Q is H, halo, CN, NO₂, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ haloalkyl, halosulfanyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ haloalkyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl,C₁₋₄ cyanoalkyl, Cy², CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′),C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′),NR^(c′)R^(d′), NR^(c′)C(O)R^(b′), NR^(c′)C(O)NR^(c′)R^(d′),NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′),NR^(c′)S(O)₂R^(b′), and S(O)₂NR^(c′)R^(d′);

Cy¹ and Cy² are independently selected from aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2,3, 4 or 5 substituents independently selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″),C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″),NR^(c″)R^(d″), NR^(c″)C(O)R^(b″), NR^(c″)C(O)OR^(a″), NR^(c″)S(O)R^(b″),NR^(c″)S(O)₂R^(b″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), andS(O)₂NR^(c″)R^(d″);

R¹, R², R³, and R⁴ are independently selected from H, halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸,C(O)NR⁹R¹⁰, C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸,NR^(c)C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and S(O)₂NR⁹R¹⁰;

R⁵ is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,halosulfanyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, OC(O)R⁸,OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸,NR⁹S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;

R⁶ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, OR⁷,C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, orS(O)₂NR⁹R¹⁰;

R⁷ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl;

R⁸ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl;

R⁹ and R¹⁰ are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylcarbonyl, arylcarbonyl,C₁₋₆ alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl andheterocycloalkylalkyl;

or R⁹ and R¹⁰ together with the N atom to which they are attached form a4-, 5-, 6- or 7-membered heterocycloalkyl group;

R¹¹ and R¹² are independently selected from H and -E¹-E²-E³-E⁴;

D¹ and E¹ are independently absent or independently selected from C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene, cycloalkylene,heteroarylene, and heterocycloalkylene, wherein each of the C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene, cycloalkylene,heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN,OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylamino, and C₂₋₈ dialkylamino;

D² and E² are independently absent or independently selected from C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, (C₁₋₆ alkylene)_(r)-O—(C₁₋₆alkylene), (C₁₋₆ alkylene)_(r)-S—(C₁₋₆ alkylene)_(s), (C₁₋₆alkylene)_(r)-NR^(e)—(C₁₋₆ alkylene)_(s), (C₁₋₆ alkylene)_(r)-CO—(C₁₋₆alkylene)_(s), (C₁₋₆ alkylene)_(r)-COO—(C₁₋₆ alkylene)_(s), (C₁₋₆alkylene)_(r)-CONR^(e)—(C₁₋₆ alkylene)_(s), (C₁₋₆alkylene)_(r)-SO₂—(C₁₋₆ alkylene)_(s), (C₁₋₆ alkylene)_(r)-SO₂—(C₁₋₆alkylene)_(s), (C₁₋₆ alkylene)_(r)-SONR^(e)—(C₁₋₆ alkylene)_(s), and(C₁₋₆ alkylene)_(r)-NR^(e)CONR^(f)—(C₁₋₆ alkylene)_(s), wherein each ofthe C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,CN, NO₂, N₃, SCN, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkoxyalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, and C₂₋₈ dialkylamino;

D³ and E³ are independently absent or independently selected from C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene, cycloalkylene,heteroarylene, and heterocycloalkylene, wherein each of the C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene, cycloalkylene,heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN,OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylamino, and C₂₋₈ dialkylamino;

D⁴ and E⁴ are independently selected from H, halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl,C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆alkyl)R^(b), and S(O)₂NR^(c)R^(d), wherein said C₁₋₈ alkyl, C₂₋₈alkenyl, or C₂₋₈ alkynyl, is optionally substituted with 1, 2, 3, 4, 5,or 6 substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl,C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆alkyl))R^(b), and S(O)₂NR^(c)R^(d);

R^(a) is H, Cy¹, —(C₁₋₆ alkyl)-Cy¹, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^(b) is H, Cy¹, —(C₁₋₆ alkyl)-Cy¹, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^(a′)and R^(a″) are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl andheterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl;

R^(b′) and R^(b″) are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl andheterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl and heterocycloalkyl;

R^(c) and R^(d) are independently selected from H, Cy¹, —(C₁₋₆alkyl)-Cy¹, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl,is optionally substituted with 1, 2, or 3 substituents independentlyselected from Cy¹, —(C₁₋₆ alkyl)-Cy¹, OH, CN, amino, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, and halosulfanyl;

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy¹, —(C₁₋₆ alkyl)-Cy¹, OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkyl, and halosulfanyl;

R^(c′) and R^(d′) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl andheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl and heterocycloalkyl;

or R^(c′) and R^(d′) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl,halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl;

R^(c″) and R^(d″) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl andheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,halosulfanyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl;

or R^(c″) and R^(d″) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl,halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl;

R^(i) is H, CN, NO₂, or C₁₋₆ alkyl;

R^(e) and R^(f) are independently selected from H and C₁₋₆ alkyl;

R^(i) is H, CN, or NO₂;

m is 0 or 1;

n is 0 or 1;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 0, 1, 2, 3, 4, 5 or 6;

r is 0 or 1; and

s is 0 or 1.

In some embodiments, when X is N, n is 1, and the moiety formed by A¹,A², U, T, V, and —(Y)_(n)—Z has the formula:

then Y is other than (CR¹¹R¹²)_(p)C(O)NR(CR¹¹R¹²)_(q).

In some embodiments, when X is N, the 5-membered ring formed by A¹, A²,U, T, and V is other than pyrrolyl.

In some embodiments, when X is CH, n is 1, and the moiety formed by A¹,A², U, T, V, and —(Y)_(n)—Z has the formula:

then —(Y)_(n)—Z is other than COOH.

In some embodiments, when X is CH or C-halo, R¹, R², and R³ are each H,n is 1, and the moiety formed by A¹, A², U, T, V, and —(Y)_(n)—Z has theformula:

then Y is other than (CR¹¹R¹²)_(p)C(O)NR(CR¹¹R¹²)_(q) or(CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q).

In some embodiments, when X is CH or C-halo, R¹, R², and R³ are each H,n is 0, and the moiety formed by A¹, A², U, T, V, and —(Y)_(n)—Z has theformula:

then Y is other than (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q) or(CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q).

In some embodiments, when X is CH or C-halo, R¹, R², and R³ are each H,n is 1, and the moiety formed by A¹, A², U, T, V, and —(Y)_(n)—Z has theformula:

then Y is other than (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q), or(CR³¹R³²)_(p)C(O)CR¹¹R¹²)_(q).

In some embodiments, when X is CH or C-halo, R¹, R², and R³ are each H,n is 1, and the moiety formed by A¹, A², U, T, V, and —(Y)_(n)—Z has theformula:

then Y is other than (CR¹¹R¹²)_(p)NR^(c)(CR¹¹R¹²)_(q).

In some embodiments, when X is CH or C-halo and R¹, R², and R³ are eachH, then the moiety formed by A¹, A², U, T, V, and —(Y)_(n)—Z has aformula other than:

In some embodiments:

Z is H, halo, CN, NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, whereinsaid C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ haloalkyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substitutedwith 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

Q is H, halo, CN, NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, whereinsaid C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ haloalkyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,C₁₋₄ cyanoalkyl, Cy², CN, NO₂, OR^(a′), SR^(a′), C(O)R^(b′),C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′), OC(O)NR^(c′)R^(d′),NR^(c′)R^(d′), NR^(c′)C(O)R^(b′), NR^(c′)C(O)NR^(c′)R^(d′),NR^(c′)C(O)OR^(a′), S(O)R^(b′), S(O)NR^(c′)R^(d′), S(O)₂R^(b′),NR'S(O)₂R^(b′), and S(O)₂NR^(c′)R^(d′);

Cy¹ and Cy² are independently selected from aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2,3, 4 or 5 substituents independently selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″),C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″),NR^(c″)C(O)R^(b″), NR^(c″)C(O)OR^(a″), NR^(c″)S(O)R^(b″),NR^(c″)S(O)₂R^(b″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), andS(O)₂NR^(c″)R^(d″), R¹, R², R³, and R⁴ are independently selected fromH, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸,C(O)NR⁹R¹⁰, C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸,NR^(c)C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and S(O)₂NR⁹R¹⁰;R⁵ is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, OC(O)R⁸, OC(O)NR⁹R¹⁰,NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸,or S(O)₂NR⁹R¹⁰; R⁶ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, OR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰,S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;

R⁷ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl;

R⁸ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl;

R⁹ and R¹⁰ are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylcarbonyl, arylcarbonyl,C₁₋₆ alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl andheterocycloalkylalkyl;

or R⁹ and R¹⁰ together with the N atom to which they are attached form a4-, 5-, 6- or 7-membered heterocycloalkyl group;

R¹¹ and R¹² are independently selected from H, halo, OH, CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;

R^(a), R^(a′), and R^(a′) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl and heterocycloalkyl;

R^(b), R^(b′) and R^(b″), are independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^(c) and R^(d) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl andheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl orheterocycloalkyl;

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^(c′)and R^(d′) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl andheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl andheterocycloalkyl;

or R^(c′)and R^(d′) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^(c″) and R^(d″) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl andheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl andheterocycloalkyl; and

or R^(c″) and R^(d″) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl.

In some embodiments, X is N.

In some embodiments, X is CR⁴.

In some embodiments, A¹ is C.

In some embodiments, A¹ is N.

In some embodiments, A² is C.

In some embodiments, A² is N.

In some embodiments, at least one of A¹, A², U, T, and V is N.

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or oxadiazolyl.

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis selected from:

wherein:

a designates the site of attachment of moiety —(Y)_(n)—Z;

b designates the site of attachment to the core moiety:

and

c and c′ designate the two sites of attachment of the fused 4- to20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring.

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis selected from:

wherein:

a designates the site of attachment of moiety —(Y)_(n)—Z;

b designates the site of attachment to the core moiety:

and

c and c′ designate the two sites of attachment of the fused 4- to20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring.

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis selected from:

wherein:

a designates the site of attachment of moiety —(Y)_(n)—Z;

b designates the site of attachment to the core moiety:

and

c and c′ designate the two sites of attachment of the fused 4- to20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring.

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis selected from:

wherein:

a designates the site of attachment of moiety —(Y)_(n)—Z;

b designates the site of attachment to the core moiety:

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis selected from:

wherein:

a designates the site of attachment of moiety —(Y)_(n)—Z;

b designates the site of attachment to the core moiety:

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis selected from:

wherein:

a designates the site of attachment of moiety —(Y)_(n)—Z;

b designates the site of attachment to the core moiety:

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 1 and Y is C₁₋₈ alkylene, C₂₋₈ alkenylene,(CR¹¹R¹²)C(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)OC(O)(CR¹¹R¹²)_(q),wherein said C₁₋₈ alkylene or C₂₋₈ alkenylene, is optionally substitutedwith 1, 2, or 3 halo, OH, CN, amino, C₁₋₄ alkylamino, or C₂₋₈dialkylamino.

In some embodiments, n is 1 and Y is C₁₋₈ alkylene,(CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)C(O)NR(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q), wherein said C₁₋₈ alkylene isoptionally substituted with 1, 2, or 3 halo, OH, CN, amino, C₁₋₄alkylamino, or C₂₋₈ dialkylamino.

In some embodiments, n is 1 and Y is C₁₋₈ alkylene optionallysubstituted with 1, 2, or 3 halo, OH, CN, amino, C₁₋₄ alkylamino, orC₂₋₈ dialkylamino.

In some embodiments, n is 1 and Y is ethylene optionally substitutedwith 1, 2, or 3 halo, OH, CN, amino, C₁₋₄ alkylamino, or C₂₋₈dialkylamino.

In some embodiments, n is 1 and Y is (CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q)(CR¹¹R¹²)_(p)C(O)NR^(c)—(CR¹¹R¹²)_(q), or(CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q).

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, (CR¹¹R¹²)_(p)—(C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(arylene)-(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)—(C₁₋₁₀heterocycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(heteroarylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)O(CR¹¹R¹²)_(q), or (CR¹¹R¹²)_(p)S(CR¹¹R¹²)_(q), whereinsaid C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene, cycloalkylene,arylene, heterocycloalkylene, or heteroarylene, is optionallysubstituted with 1, 2, or 3 substituents independently selected from-D¹-D²-D³-D⁴.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, (CR¹¹R¹²)_(p)—(C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(arylene)-(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)—(C₁₋₁₀heterocycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(heteroarylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)O(CR¹¹R¹²)_(q), or (CR¹¹R¹²)_(p)S(CR¹¹R¹²)_(q), whereinsaid C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene, cycloalkylene,arylene, heterocycloalkylene, or heteroarylene, is optionallysubstituted with 1, 2, or 3 substituents independently selected from D⁴.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, or (CR¹¹R¹²)_(p)—(C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),wherein said C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene, orcycloalkylene, is optionally substituted with 1, 2, or 3 substituentsindependently selected from -D¹-D²-D³-D⁴.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, or (CR¹¹R¹²)_(p)—(C₃. 10 cycloalkylene)-(CR¹¹R¹²)_(q),wherein said C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene, orcycloalkylene, is optionally substituted with 1, 2, or 3 substituentsindependently selected from D⁴.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, or C₂₋₈alkynylene, each optionally substituted with 1, 2, or 3 substituentsindependently selected from -D¹-D²-D³-D⁴.

In some embodiments, Y is C₁₋₈ alkylene optionally substituted with 1,2, or 3 substituents independently selected from -D¹-D²-D³-D⁴.

In some embodiments, Y is C₁₋₈ alkylene optionally substituted with 1,2, or 3 substituents independently selected from D⁴.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, (CR¹¹R¹²)_(p)O—(CR¹¹R¹²)_(q), (CR¹¹R¹²)S(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)OC(O)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)OC(O)NR^(c)(CR¹¹R¹²)_(q), (CR¹ 1R¹²)_(p)NR(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)NR^(c)C(O)NR^(d)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)S(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)S(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)S(O)₂(CR¹¹R¹²)_(q), or(CR¹¹R¹²)_(p)S(O)₂NR^(c)(CR¹¹R¹²)_(q), wherein said C₁₋₈ alkylene, C₂₋₈alkenylene, C₂₋₈ alkynylene is optionally substituted with 1, 2, or 3substituents independently selected from halo, OH, CN, amino, C₁₋₄alkylamino, and C₂₋₈ dialkylamino.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, (CR¹¹R¹²)_(p)—(C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(arylene)-(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)—(C₁₋₁₀heterocycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(heteroarylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)S(CR¹¹R¹²)_(q),(CR¹¹R¹²)C(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)OC(O)(CR¹¹R¹²)_(q), (CR¹1R¹²)_(p)OC(O)NR^(c)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)NR^(c)(CR¹¹R¹²)_(q),(CR¹ 1R¹²)_(p)NR^(c)C(O)NR^(d)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)S(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)S(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)S(O)₂(CR¹¹R¹²)_(q), or(CR¹¹R¹²)_(p)S(O)₂NR^(c)(CR¹¹R¹²)_(q), wherein said C₁₋₈ alkylene, C₂₋₈alkenylene, C₂₋₈ alkynylene, cycloalkylene, arylene,heterocycloalkylene, or heteroarylene, is optionally substituted with 1,2, or 3 substituents independently selected from halo, OH, CN, amino,C₁₋₄ alkylamino, and C₂₋₈ dialkylamino.

In some embodiments, p is 0.

In some embodiments, p is 1.

In some embodiments, p is 2.

In some embodiments, q is 0.

In some embodiments, q is 1.

In some embodiments, q is 2.

In some embodiments, one of p and q is 0 and the other of p and q is 1,2, or 3.

In some embodiments, Z is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl)R^(b), andS(O)₂NR^(c)R^(d), wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl))R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹,CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl,C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4,5, or 6 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4,5, or 6 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl, each optionally substituted with 1, 2, 3, 4,5, or 6 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl,each optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsselected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl,each optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsselected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹,CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4, 5, or 6 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4, 5, or 6 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4,5, or 6 substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl,C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4,5, or 6 substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl,each optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl,each optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substitutedwith 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), C(O)NR^(c)R^(d), C(O)OR^(a),NR^(c)R^(d), NR^(c)C(O)R^(b), and S(O)₂R^(b).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substitutedwith 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d), NR^(c)C(O)R^(b),and S(O)₂R^(b).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl,Cy¹, CN, NO₂, OR^(a), C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d),NR^(c)C(O)R^(b), and S(O)₂R^(b).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂,OR^(a), C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d), NR^(c)C(O)R^(b), andS(O)₂R^(b).

In some embodiments, Z is substituted with at least one substituentcomprising at least one CN group.

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with atleast one CN or C₁₋₄ cyanoalkyl and optionally substituted with 1, 2, 3,4, or 5 further substituents selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl,C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with atleast one CN or C₁₋₄ cyanoalkyl and optionally substituted with 1, 2, 3,4, or 5 further substituents selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, wherein the —(Y)_(n)—Z moiety is taken togetherwith i) A² to which said moiety is attached, ii) R⁵ or R⁶ of either T orV, and iii) the C or N atom to which said R⁵ or R⁶ of either T or V isattached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, orheterocycloalkyl ring fused to the 5-membered ring formed by A¹, A², U,T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl,or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5substituents independently selected from —(W)_(m)-Q.

In some embodiments, wherein the —(Y)_(n)—Z moiety is taken togetherwith i) A² to which said moiety is attached, ii) R⁵ or R⁶ of either T orV, and iii) the C or N atom to which said R⁵ or R⁶ of either T or V isattached to form a 4- to 8-membered aryl, cycloalkyl, heteroaryl, orheterocycloalkyl ring fused to the 5-membered ring formed by A¹, A², U,T, and V, wherein said 4- to 8-membered aryl, cycloalkyl, heteroaryl, orheterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5substituents independently selected from —(W)_(m)-Q.

In some embodiments, the —(Y)_(n)—Z moiety is taken together with i) A²to which said moiety is attached, ii) R⁵ or R⁶ of either T or V, andiii) the C or N atom to which said R⁵ or R⁶ of either T or V is attachedto form a 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkylring fused to the 5-membered ring formed by A¹, A², U, T, and V, whereinsaid 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ringis optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, CN, NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₈ haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkylwherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ haloalkyl,aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionallysubstituted by 1, 2 or 3 CN.

In some embodiments, Cy¹ and Cy² are independently selected from aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″),C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″),NR^(c″)R^(d″), NR^(c″)C(O)R^(b″), NR^(c″)C(O)OR^(a″), S(O)R^(b″),S(O)NR^(c″)R^(d″), S(O)₂R^(b″), and S(O)₂NR^(c″)R^(d″).

In some embodiments, Cy¹ and Cy² are independently selected from aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂,OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(b″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), andS(O)₂NR^(c″)R^(d″).

In some embodiments, Cy¹ and Cy² are independently selected fromcycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(b″), NR^(c″)C(O)OR^(a),S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), and S(O)₂NR^(c″)R^(d″).

In some embodiments, Cy¹ and Cy² are independently selected fromcycloalkyl optionally substituted by 1, 2, 3, 4 or 5 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″),C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″),NR^(c″)R^(d″), NR^(c″)C(O)R^(b″), NR^(c″)C(O)OR^(a″), S(O)R^(b″),S(O)NR^(c″)R^(d″), S(O)₂R^(b″), and S(O)₂NR^(c″)R^(d″).

In some embodiments, R¹, R², R³, and R⁴ are independently selected fromH, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸,C(O)NR⁹R¹⁰, C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸,NR^(c)C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and S(O)₂NR⁹R¹⁰.

In some embodiments, R¹, R², R³, and R⁴ are independently selected fromH, halo, and C₁₋₄ alkyl.

In some embodiments, R¹, R², R³, and R⁴ are each H.

In some embodiments, R¹ is H, halo, or C₁₋₄ alkyl.

In some embodiments, R⁵ is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷,OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰,S(O)₂R⁸, NR⁹S(O)₂R⁸, or S(O)₂NR⁹R¹⁰.

In some embodiments, R⁵ is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,halosulfanyl, CN, or NR⁹R¹⁰.

In some embodiments, R⁵ is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, orNR⁹R¹⁰.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is H or C₁₋₄ alkyl.

In some embodiments, R⁶ is H.

In some embodiments, R¹¹ and R¹² are independently selected from H,halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), C(═NOH)R^(b),C(═NO(C₁₋₆ alkyl)R^(b), and S(O)₂NR^(c)R^(d), wherein said C₁₋₈ alkyl,C₂₋₈ alkenyl, or C₂₋₈ alkynyl, is optionally substituted with 1, 2, 3,4, 5, or 6 substituents independently selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR¹)NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆alkyl))R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, R¹¹ and R¹² are independently selected from H,halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halosulfanyl, SCN, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl.

In some embodiments, R¹¹ and R¹² are independently selected from H,halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, aryl, heteroaryl, cycloalkyl, andheterocycloalkyl.

In some embodiments, the compound has Formula Ia or Ib:

In some embodiments, the compound has Formula II:

In some embodiments, the compound has Formula IIIa or IIIb:

In some embodiments, the compound has Formula IV:

In some embodiments, the compound has Formula Va:

In some embodiments, the compound has Formula Vb:

In some embodiments, the compound has Formula VIa:

In some embodiments, the compound has Formula VIb:

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment.

Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

At various places in the present specification, linking substituents aredescribed. It is specifically intended that each linking substituentinclude both the forward and backward forms of the linking substituent.For example, —NR(CR′R″)_(n)— includes both NR(CR′R″)_(n) and—(CR′R″)_(n)NR—. Where the structure clearly requires a linking group,the Markush variables listed for that group are understood to be linkinggroups. For example, if the structure requires a linking group and theMarkush group definition for that variable lists “alkyl” or “aryl” thenit is understood that the “alkyl” or “aryl” represents a linkingalkylene group or arylene group, respectively.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring and 1,2,3,4-tetrahydro-naphthalene isan example of a 10-membered cycloalkyl group.

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like. An alkyl group cancontain from 1 to about 20, from 2 to about 20, from 1 to about 10, from1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3carbon atoms. A linking alkyl group is referred to herein as “alkylene.”

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, cyclohexenyl, and the like. A linking alkenyl group isreferred to herein as “alkenylene.”

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like. A linking alkynyl group is referred to herein as“alkynylene.”

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like.

As used herein, “halosulfanyl” refers to a sulfur group having one ormore halogen substituents. Example halosulfanyl groups includepentahalosulfanyl groups such as SF₅.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and thelike. In some embodiments, aryl groups have from 6 to about 20 carbonatoms. A linking aryl group is referred to herein as “arylene.”

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings)groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl groupcan be optionally substituted by oxo or sulfido. Cycloalkyl groups alsoinclude cycloalkylidenes. Example cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl,cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl,norcarnyl, adamantyl, and the like. Also included in the definition ofcycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo or thienyl derivatives of pentane, pentene, hexane, andthe like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. A linking cycloalkyl group is referred toherein as “cycloalkylene.”

As used herein, “heteroaryl” refers to an aromatic heterocycle having atleast one heteroatom ring member such as sulfur, oxygen, or nitrogen.Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3or 4 fused rings) systems. Examples of heteroaryl groups include withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl,indolinyl, and the like. In some embodiments, the heteroaryl group hasfrom 1 to about 20 carbon atoms, and in further embodiments from about 3to about 20 carbon atoms. In some embodiments, the heteroaryl groupcontains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6ring-forming atoms. In some embodiments, the heteroaryl group has 1 toabout 4, 1 to about 3, or 1 to 2 heteroatoms. A linking heteroaryl groupis referred to herein as “heteroarylene.”

As used herein, “heterocycloalkyl” refers to non-aromatic heterocyclesincluding cyclized alkyl, alkenyl, and alkynyl groups where one or moreof the ring-forming carbon atoms is replaced by a heteroatom such as anO, N, or S atom. Heterocycloalkyl groups include monocyclic andpolycyclic (e.g., having 2, 3 or 4 fused rings) systems as well asspirocycles. Example “heterocycloalkyl” groups include morpholino,thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Ring-formingcarbon atoms and heteroatoms of a heterocycloalkyl group can beoptionally substituted by oxo or sulfido. Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl,and benzo derivatives of heterocycles. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. The heterocycloalkyl group containing a fused aromatic ringcan be attached through any ring-forming atom including a ring-formingatom of the fused aromatic ring. In some embodiments, theheterocycloalkyl group has from 1 to about 20 carbon atoms, and infurther embodiments from about 3 to about 20 carbon atoms. In someembodiments, the heterocycloalkyl group contains 3 to about 14, 4 toabout 14, 3 to about 7, or 5 to 6 ring-forming atoms. In someembodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3,or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl groupcontains 0 to 3 double or triple bonds. In some embodiments, theheterocycloalkyl group contains 0 to 2 double or triple bonds. A linkingheterocycloalkyl group is referred to herein as “heterocycloalkylene.”

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “arylalkyl” refers to alkyl substituted by aryl and“cycloalkylalkyl” refers to alkyl substituted by cycloalkyl. An examplearylalkyl group is benzyl.

As used herein, “heteroarylalkyl” refers to alkyl substituted byheteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted byheterocycloalkyl.

As used herein, “amino” refers to NH₂.

As used herein, “alkylamino” refers to an amino group substituted by analkyl group.

As used herein, “dialkylamino” refers to an amino group substituted bytwo alkyl groups.

As used herein, “hydroxylalkyl” refers to an alkyl group substituted byhydroxyl.

As used herein, “cyanoalkyl” refers to an alkyl group substituted bycyano. The carbon of the cyano group is typically not counted if acarbon count precedes the term. For example, cyanomethyl is consideredherein to be a C₁ cyanoalkyl group.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such as3-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methyl-benzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention further include hydrates and solvates, aswell as anhydrous and non-solvated forms.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

In some embodiments, the compounds of the invention, and salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which is was formed or detected. Partial separation caninclude, for example, a composition enriched in the compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compound of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g a reaction temperature, that is about the temperature of the room inwhich the reaction is carried out, for example, a temperature from about20° C. to about 30° C.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile (MeCN) are preferred.Lists of suitable salts are found in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418and Journal of Pharmaceutical Science, 66, 2 (1977), each of which isincorporated herein by reference in its entirety.

The present invention also includes prodrugs of the compounds describedherein. As used herein, “prodrugs” refer to any covalently bondedcarriers which release the active parent drug when administered to amammalian subject. Prodrugs can be prepared by modifying functionalgroups present in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds wherein hydroxyl, amino,sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention. Preparation and use of prodrugs is discussed in T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated by referencein their entirety.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Green and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C)infrared spectroscopy, spectrophotometry (e.g., UV-visible), or massspectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

Compounds of the invention can be prepared according to numerouspreparatory routes known in the literature. Example synthetic methodsfor preparing compounds of the invention are provided in the Schemesbelow.

As shown in Scheme 1, pyrazole-containing cores 1-9 and 1-6 can besynthesized starting with pyrrolo[2,3-b]pyridine orpyrrolo[2,3-b]pyrimidine 1-1. The compound 1-1 can be converted to anactive species such as an N-oxide analog (1-2) by using an oxidant suchas m-CPBA. The N-oxide 1-2 can be halogenated with a halogenating agentsuch as a combination of tetramethylammonium bromide and methanesulfonicanhydride to form a 4-halo compound 1-3 such as a 4-bromo compound whilethe N-oxide is reduced at the same time. The amine group of the compound1-3 can be protected by a suitable amine protecting group to afford theprotected compound 1-7, which subsequently undergoes a Suzuki couplingwith a boric acid 1-8 to afford the pyrazole-containing cores 1-9a whichcan be further reacted with reagent L-(Y)_(n)—Z (where L is a leavinggroup) to give compounds of the invention 1-9b. Alternatively, theN-oxide 1-2 can be halogenated with a halogenating agent such as MeSO₂Clto form a 4-halo compound 1-4 such as a 4-chloro compound while theN-oxide is reduced at the same time. The 4-halo compound 1-4 can becoupled to a bromo-substituted pyrazole compound 1-5 under suitableconditions such as heating to afford the pyrazole-containing core 1-6,which may contain some functional groups such as bromo or cyano suitablefor further chemical modification.

Similarly, an imidazole core 1-11 can be synthesized by coupling of the4-halo compound 1-4 to an imidazole derivative 1-10 under suitableconditions such as heating to afford the imidazole-containing core 1-11,which may contain some functional groups such as bromo or cyano suitablefor further chemical modification.

As shown in Scheme 2, pyrazole-containing cores 2-3, 2-5 and 2-6 can besynthesized starting with a bromo-substituted pyrazole derivative 2-1 (acompound 1-6 in Scheme 1 wherein one of R⁵ is Br). The bromo-substitutedpyrazole derivative 2-1 can be coupled to boron-containing aromaticspecies such as an aromatic boric acid 2-2 using Suzuki coupling whereinAr is aryl or heteroaryl, each of which can be optionally substituted byone or more substituents such as alky, aryl, CN, nitro, alkoxy, etc.Alternatively, an alkene- or alkyne-containing compound such as analkene-containing 2-5 can be obtained by coupling the bromo-substitutedpyrazole derivative 2-1 to an unsaturated compound such as an alkene 2-4in the presence of a metal catalyst such asbis(triphenylphos-phine)palladium (II) chloride wherein t can be 0, 1,2, and the like; and R can be a substituent such as alkyl, aryl, CN,nitro, alkoxy, etc. The alkene group of compound 2-5 can be reduced byhydrogenation to afford the corresponding compound 2-6.

As shown in Scheme 3, imidazole-containing cores 3-7 can be synthesizedstarting with an N-protected 4-bromo-pyrrolo[2,3-b]pyridine or anN-protected 4-bromo-pyrrolo[2,3-b]pyrimidine 3-1 wherein P is a suitableamine protecting group such as {[2-(trimethylsilyl)ethoxy]methyl} (SEM).Compound 3-1 can be reacted with a Grignard reagent such as isopropylmagnesium chloride to generate an aromatic anion through ion exchange.The subsequent addition of a chloroacetyl-containing compound such as2-chloro-N-methoxy-N-methylacetamide 3-2 to the anion will typicallyafford the chloroacetyl derivative 3-3. The derivative 3-3 can bereacted with an organic acid salt such as a cesium salt R⁵CO₂Cs toafford a compound 3-4. In the presence of a suitable ammonia source suchas ammonium acetate, the compound 3-4 can react with ammonia undersuitable conditions such as at a high temperature to form the imidazolering of the compound 3-5. The free amine nitrogen of the imidazolederivative 3-5 can undergo further modification such as reacting with acompound X—(Y)_(n)—Z where X is a leaving group such as chloro, bromo oriodo so as to afford compound 3-6. The protecting group of compound 3-6can be removed by an appropriate method according to the nature of theprotecting group to yield compound 3-7. It should be noted that if thereare functional groups present within the R, R⁵, and —(Y)_(n)—Z group,further modification can be made. For example, a CN group can behydrolyzed to afford an amide group; a carboxylic acid can be convertedto a ester, which in turn can be further reduced to an alcohol, which inturn can be further modified. One skilled in the art will recognizeappropriate further modifications.

As shown in Scheme 4, thiazole-containing cores 4-3 can be synthesizedstarting with an N-protected chloroacetyl derivative 4-1 wherein P is asuitable amine protecting group such as SEM. Compound 4-1 can be reactedwith a thioamide 4-2 to form the thiazole ring, followed by deprotectionof the amine nitrogen of the pyrrole ring by removal of the P group toafford the compound 4-3. Various thioureas 4-5 (equivalent to compound4-2 wherein —(Y)_(n)—Z is NR′R″; and R′ and R″ are H, alkyl, aryl or thelike; or R′ and R″ together with the N atom to which they are attachedform a heterocycloalkyl) useful in preparing the thiazole compounds 4-3can be made from secondary amines 4-4. A secondary amine 4-4 can bereacted with 1,1′-thiocarbonyldiimidazole; and the resultingintermediate can further be reacted with ammonia to afford a thiourea4-5.

As shown in Scheme 5, thiazole-containing cores 5-5 can be synthesizedstarting with a thiazole compound 5-1. The compound 5-1 can be reactedwith a metal alkyl such as n-butyl lithium via ion exchange to generatean aromatic anion in situ. The subsequent addition of boric acidtrimethyl ester followed by hydrolysis will typically afford the boricacid 5-2. The boric acid 5-2 can undergo Suzuki coupling with anN-protected 4-bromo-pyrrolo[2,3-b]pyridine or an N-protected4-bromo-pyrrolo[2,3-b]pyrimidine 5-3 wherein P is a suitable amineprotecting group such as SEM. The protecting group P of the couplingproduct 5-4 can be removed by an appropriate method according to thenature of the protecting group to yield the compound of the invention5-5.

As shown in Scheme 6, pyrazole-containing compounds 6-1 can further bemodified by substitution on the pyrazole NH group with appropriatereagents. For example, a compound 6-1 wherein P is a suitable amineprotecting group such as SEM can be reacted with L-(Y)_(n)—Z where Lrepresents a leaving group such as halo, triflate or the like to affordcompound 6-2 under basic condition. If there are some functional groupspresent within the Y and/or Z group, further modification can be made.For example, a CN group can be hydrolyzed to afford an amide group; acarboxylic acid can be converted to a ester, which in turn can befurther reduced to alcohol. One skilled in the art will recognize thefurther modifications if appropriate.

Additionally, compound 6-1 can be reacted with alkene 6-3 (wherein R′and R″ can be H, alkyl, cycloalkyl and the like; and Z′ can be anelectron withdrawing group such as an ester or CN) to afford thecompound 6-4. Further, substitution can be made on alkene 6-3 at thealpha position (alpha to Z′) to generate a substituted derivatives ofproduct, 6-4 (see, e.g., Example 68).

Compounds 6-2 and 6-4 can be deprotected by appropriate methodsaccording to the nature of the protecting group used to afford theircorresponding de-protected counterpart.

As shown in Scheme 7, bromo pyrazole containing compounds 7-1 can befurther modified by metallation with reagents like butyl lithium andreaction with electrophiles like aldehydes to give the alcoholcontaining compounds 7-2 which can be deprotected to yield compounds ofthe invention having formula 7-3. One skilled in the art will recognizethe further modifications where appropriate.

As shown in Scheme 8, pyrazole-containing compounds 8-4 and 8-5 can beprepared by reaction of the N-protected bromo compound 8-1 withhydrazine in an appropriate solvent such as N,N-dimethylformamide (DMF)to give the hydrazine intermediate 8-2. The hydrazino intermediate 8-2is reacted with an appropriately substituted 1,3 bis-aldehyde like 8-3to give the pyrazole containing compound 8-4. If there are somefunctional groups present within the Y and/or Z group, furthermodification can be made. For example, a CN group can be hydrolyzed toafford an amide group; a carboxylic acid can be converted to a ester,which in turn can be further reduced to alcohol. One skilled in the artwill recognize further potential modifications.

As shown in Scheme 9, the 1,2,4-oxadiazole compound 9-6 can preparedfrom the N-protected bromo compound 9-1 by treatment with zinc cyanidein DMF in the presence of a catalyst like bis(tributyl) palladium togive the N-protected cyano compound 9-2. The N-hydroxy carboximidamidecompound 9-3 can be prepared by heating the N-protected cyano compound9-2 with hydroxylamine hydrochloride in an appropriate solvent likeethanol and a base like potassium carbonate at a temperature below theboiling point of the solvent. The N-protected 1,2,4-oxadiazole compoundcan be prepared by treating the N-hydroxy carboximidamide compound 9-3with an appropriately substituted acid chloride compound 9-4 in asolvent like pyridine at a sufficient temperature to complete the ringclosure. If there are some functional groups present within the Y and/orZ group, further modification can be made. For example, a CN group canbe hydrolyzed to afford an amide group; a carboxylic acid can beconverted to an ester, which in turn can be further reduced to alcohol.One skilled in the art will recognize further modifications whereappropriate.

As shown in Scheme 10, the 3- and 4-arylpyrazolo compounds 10-9 can beprepared by reaction of the respective 3-arylpyrazolo compound 10-4 or4-aryl pyrazolo compound 10-7 with an appropriately substituted bromocompound 10-8 as previously described. The 3-aryl pyrazolo compound 10-4can be prepared by reacting an appropriately substituted aryl groupcontaining a halogen like bromo or a triflate with the N-protectedboronic acid or boronic acid ester pyrazole compound 10-2 underSuzuki-like conditions known in the literature. The N-protecting groupof 10-3 can be removed by conditions previously described and known inthe literature for removing groups like SEM.

The 4-arylpyrazolo compounds 10-7 can be prepared by reacting theappropriately substituted acetophenone compound 10-5 with DMF acetal inDMF at elevated temperatures to give the dimethylamino compound 10-6.The 4-arylpyrazolo compounds 10-7 can be prepared by treating thedimethylamino compound 10-6 with hydrazine in a solvent such as ethanol.

As shown in Scheme 11 the substituted pyrazole compound 11-5 can beprepared by a variety of methods, such as by removing the protectinggroup e.g., SEM from compound 11-4 under conditions previouslydescribed. For example the substituted pyrazole N-protected compound11-4 can be prepared by reaction of the intermediate pyrazoleN-protected compound 11-3 with an appropriately substituted alkylhalide, benzyl halide, alkyl sulfonates, e.g., mesylate or tosylate, orother suitable leaving group L, in an appropriate solvent such as MeCN,DMF or tetrahydrofuran (THF), in the presence of a base such a sodiumhydride or cesium carbonate. The N-aryl pyrazole 11-4 (wherein Y isaromatic) may be prepared by reacting the intermediate pyrazole 11-3with an appropriately substituted aryl boronic acid in a solvent such asdichloromethane (DCM) with copper acetate and pyridine. Alternativelythe N-aryl pyrazole 11-4 (wherein Y is aromatic) can be prepared byreacting the intermediate pyrazole 11-3 with an appropriatelysubstituted aryl-fluoride in a solvent such as DMF at elevatedtemperature. Or, the substituted pyrazole compounds 11-4 (wherein Z is agroup such as nitrile or ester and Y is at least two carbons) can beprepared by the reaction of intermediate pyrazole 11-3 with anappropriately substituted acrylate, acrylonitrile or other Michael-likeacceptors in a solvent such as DMF in the presence of a base such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or triethylamine (TEA) and at atemperature below the boiling point of the solvent. If there are somefunctional groups present within the Y and/or Z group, furthermodification can be made. For example, a CN group can be hydrolyzed toafford an amide group; a carboxylic acid can be converted to a ester,which in turn can be further reduced to alcohol. One skilled in the artwill recognize the further modifications if appropriate.

As shown in Scheme 12, pyrazole 12-1 wherein P is a suitable amineprotecting group such as SEM can be reacted with an alkyne-containingconjugate acceptor such as 12-2, wherein Z is an electron-withdrawinggroup (for example, —CN) optionally in the presence of a base (DBU orK₂CO₃ and the like) in a solvent such as DMF or MeCN for variablelengths of time to provide olefin-containing adducts 12-3. Compoundsrepresented by the formula 12-3 can be deprotected by appropriatemethods according to the nature of the protecting group used to affordcompounds of the invention 12-4.

As shown in Scheme 13, oxazole- or thiazole-containing compounds 13-6can be prepared starting with N-protected4-chloro-pyrrolo[2,3-b]pyrimidine 13-1 wherein P is a suitable amineprotecting group such as SEM. Oxazole- or thiazole-containing productsof formula 13-2 can be prepared by palladium-catalyzed coupling of 13-1with oxazole or thiazole. The compound 13-2 can be reacted with a metalalkyl such as n-butyllithium to generate the aromatic anion in situ towhich can be added at low temperatures (preferably between −78° C. and0° C.) derivatives of carboxylic acids 13-3 (wherein W═N(Me)(OMe) whenX¹═S; and W═Cl when X¹═O), in the presence of other additives such aszinc chloride and copper(I) iodide when X¹═O, in a suitable solvent suchas THF to generate a variety of ketones 13-4. Ketones 13-4 can be causedto react with a variety of reagents such as diethyl(cyanomethyl)phosphonate or triethylphosphonoacetate in the presence ofa base like potassium tert-butoxide followed by reduction (includinghydrogenation or a copper-hydride catalyzed conjugate reduction), orwith reagents such as tosylmethyl isocyanide to provide products offormula 13-5 wherein Z is an electron-withdrawing group such as ester or—CN. If there are functional groups present within the R group orencompassed by the Z group, further modification can be made, and suchappropriate further modifications will be recognized by one skilled inthe art. Compounds 13-5 can be deprotected by appropriate methodsaccording to the nature of the protecting group used to afford theircorresponding deprotected counterparts 13-6.

As shown in Scheme 14, aminothiazole-containing cores 14-5 can besynthesized starting with thiazole-containing core 14-1 wherein P is asuitable amine protecting group such as SEM. The compound 14-1 can betreated with a metal alkyl such as n-butyllithium to generate thearomatic anion in situ to which can be added a suitable source ofelectrophilic halogen such as carbon tetrabromide to afford thehalogenated derivative 14-2. The protecting group P of 14-2 can beremoved by an appropriate method according to the nature of theprotecting group to yield product 14-3. The compound 14-3 can be reactedwith amines 14-4 at elevated temperatures in a suitable solvent such asDMF to afford the compound of the invention, 14-5.

As shown in Scheme 15, pyrrole-containing cores 15-4 can be synthesizedstarting with N-protected 4-chloro-pyrrolo[2,3-b]pyrimidine 15-1 whereinP is a suitable amine protecting group such as DEM (diethoxymethyl). Thecompound 15-1 can be reacted with 1-(triisopropylsilyl)pyrrole-3-boronicacid under Suzuki coupling conditions to afford the simultaneouslypyrrole-deprotected core 15-2. Pyrrole-containing compounds 15-2 can bereacted with alkenes 15-3 containing an electron-withdrawing group Z(such as —CN) in the presence of an appropriate base (such as DBU) atvarious temperatures (e.g., between room temperature and 40° C.)followed by an in situ or separate deprotection step that is suitablefor the selected protecting group to afford compounds of the invention15-4.

As shown in Scheme 16, a substituted pyrazole compound containing asulfone or sulfoxide functionality as in 16-6 can be prepared by avariety of methods, such as starting with an appropriately substitutedbromo thiophenyl ether 16-2. Thioether 16-2 may be readily prepared byalkylation of the thiophenol 16-1 with an alkyl halide, mesylate or thelike using a base like DBU, potassium carbonate or sodium hydride. Thecinnamyl nitrile 16-3 may be prepared by Heck chemistry and the like,using palladium acetate and triphenylphosphine in DMF at an appropriatetemperature with acrylonitrile. The SEM protected intermediate 16-4 maybe prepared by methods previously described for performing the Michaellike addition of the pyrazole core to an appropriately substituted α-βunsaturated nitrile like 16-3. The sulfoxide 16-5, where n=1, andsulfone 16-5, where n=2, may be prepared by methods well known in theliterature for the oxidation of the thio ether 16-4 likem-chloroperbenzoic acid (MCPBA) in DCM. The final compounds 16-6, wheren=0, 1 or 2, may be prepared by methods previously described for theremoval of the SEM protecting group. Alternatively, the sulfur oxidationmay be performed on compounds 16-2 or 16-3 depending on thecompatibility of the substitution in the synthetic scheme.

Also, as shown in Scheme 17, substituted pyrazole compounds containing asulfonamide functionality, such as 17-6 can be prepared by a variety ofmethods. For example, one may start with an appropriately substitutedbromo phenyl sulfonamide 17-2, where R^(c) and R^(d) are suitablesubstituents. A compound 17-2 may be readily prepared by reaction of thebromo phenyl sulfonyl chloride 17-1 and an appropriately substitutedamine such as an aniline, or a primary or secondary amine in a suitablesolvent such as DCM, THF or pyridine. The cinnamyl nitrile 17-3 may beprepared by Heck chemistry or the like, using palladium acetate andtriphenylphosphine in DMF at an appropriate temperature withacrylonitrile. The final compounds 17-6 where R^(c) and R^(d) are partof the sulfonamide functional group may be prepared by methods analogousto those described in Scheme 16 starting with the cinnamyl nitrile 17-3.

Also, as shown in Scheme 18, substituted pyrazole compounds containingan alpha-allyl cyclopentylmethylene functionality, such as 18-8, can beprepared by, for example, reacting a pyrazole 18-3, wherein P is asuitable amine protecting group such as SEM and X is N or C, with acyclopentylacrylate ester 18-4 to form the ester 18-5. The ester 18-5may then be reduced to the corresponding aldehyde, 18-6, for example, bythe two-step procedure of reducing to the alcohol and selectivelyoxidizing the intermediate alcohol to the aldehyde, e.g., via a Swernoxidation. The aldehyde, 18-6, may then be converted to thecorresponding olefin, 18-7, for example by reaction with a Wittigreagent. The olefin 18-7, may then be deprotected, as described earlier,to produce the formula 18-7 compound. The intermediate, 18-4, may beprepared, for example as shown in Scheme 18, stearting withcyclopentylaldehyde.

Also, as shown in Scheme 19, the cyanoguanidine derivative 19-6 can beprepared starting from substituted pyrazole compounds such as pyrazole18-3, wherein P is a suitable protecting group such as SEM and X is N orC. A compound 18-3 may, for example, be reacted with olefin 19-1,prepared by Horner-Wadsworth Emmons reaction of the correspondingBoc-protected piperidone, in the presence of a suitable basic catalyst,in a suitable solvent, to form 19-2. The intermediate 19-2 isdeprotected using a suitable deprotection reaction, to provide the aminecompound 19-3, which then reacts selectively with a cyanoimidocarbonatereagent such as 19-4, in a polar solvent at a suitable temperature, forexample, about 20° C. to give a cyanoimidocarbamate such as 19-5, whichcan then be reacted with any of a variety of amines at elevatedtemperature to give product 19-6.

The intermediate compounds 20-5 and 20-6 may be prepared by a variety ofmethods in the literature, for example, methods such as are outlined inScheme 20. The intermediate compound 20-3 may be prepared by reaction ofthe aldehyde compound 20-1 with an appropriately substituted Wittigreagent or Horner Emmons reagents to give the α-β unsubstituted ester20-3. Alternatively, 20-3 may be prepared by a Heck-like reaction withan appropriately substituted aryl bromide 20-2 and an acrylic ester inthe presence of a palladium reagent at elevated temperatures. Thecompound 20-4 may be prepared by methods previously described for theMichael-like addition of an appropriately substituted pyrrole 18-3 onthe α-β unsaturated ester compound 20-3. The aldehyde compound 20-5 maybe prepared by reduction of the ester compound 20-4 with reagents suchas diisobutyl aluminium hydride at low temperatures such as about −78°C. in an appropriate solvent. The aldehyde compound 20-5 can be furtherreduced to the corresponding alcohol compound 20-6 with reagents such assodium borohydride in methanol. Alternatively the alcohol compound 20-6may be prepared directly by reduction of the ester 20-4 with reagentssuch as lithium aluminium hydride in appropriate solvent and atappropriate temperatures.

The compounds 21-2 and 21-3 may be prepared by using a variety ofmethods in the literature, such as, for example, methods outlined inScheme 21. The olefin compound 21-1 may be prepared by the reaction ofaldehyde compound 20-5 with an appropriately substituted Wittig reagentor Horner Emmons reagents using a base such as sodium hydride orpotassium t-butoxide in an appropriate solvent and conducted attemperature. The olefin compound compound 21-1 may be reduced to thesaturated compound 21-2, for example, using hydrogenation conditionswell known in the literature, e.g., hydrogen in the presence ofpalladium on carbon in a solvent such as methanol. The acetyleniccompound 21-3 may be prepared by methods previously described, or byreaction of the aldehyde 20-5 with Bestmann-Ohira reagent (E. Quesada etal, Tetrahedron, 62 (2006) 6673-6680) as described in the literature.Alternatively the alcohol compound 20-6 in Scheme 20 may be oxidized tothe aldehyde 20-5 with methods well known in the literature, e.g., Swernoxidation conditions, followed by reaction with the Bestmann-Ohirareagent, wherein this reaction sequence may be carried out either as aone pot two-step reaction sequence, or in two separate reaction steps.

The compounds 22-1 and 22-3 may be prepared by using a variety ofmethods in the literature, for example, via methods outlined in Scheme22. The oxygen-substituted compound 22-1 may be prepared, for example,by reaction of an appropriately substituted alcohol 20-6 (in Scheme 20),wherein X is N or C, and P is a protecting group, with a base such assodium hydride and an appropriate agent such as an alkyl iodide,carbonate, or isocyanate, carried out in a suitable solvent and at asuitable temperature. Alternatively, the alcohol group on the compound20-6 may be converted to a leaving group LG, as in compound 22-2, wherethe leaving group can be, for example, bromide or mesylate. The compound22-2 serves as a substrate for subsequent reaction with a nucleophile,such as, for example, sodium ethoxide (Nuc=ethoxy).

It should noted that in all of the Schemes described herein, if thereare functional groups present on a substituent group such as Y, Z, R,R¹, R², R⁵, etc., further modification can be made if appropriate anddesired. For example, a CN group can be hydrolyzed to afford an amidegroup; a carboxylic acid can be converted to a ester, which in turn canbe reduced to an alcohol, which in turn can be further modified. Inanother example, an OH group can be converted into a better leavinggroup such as mesylate, which in turn is suitable for nucleophilicsubstitution, such as by CN. One skilled in the art will recognize suchfurther modifications.

Methods

Compounds of the invention can modulate activity of one or more Januskinases (JAKs). The term “modulate” is meant to refer to an ability toincrease or decrease the activity of one or more members of the JAKfamily of kinases. Accordingly, compounds of the invention can be usedin methods of modulating a JAK by contacting the JAK with any one ormore of the compounds or compositions described herein. In someembodiments, compounds of the present invention can act as inhibitors ofone or more JAKs. In some embodiments, compounds of the presentinvention can act to stimulate the activity of one or more JAKs. Infurther embodiments, the compounds of the invention can be used tomodulate activity of a JAK in an individual in need of modulation of thereceptor by administering a modulating amount of a compound of FormulaIa, Ib, or Ic.

JAKs to which the present compounds bind and/or modulate include anymember of the JAK family. In some embodiments, the JAK is JAK1, JAK2,JAK3 or TYK2. In some embodiments, the JAK is JAK1 or JAK2. In someembodiments, the JAK is JAK2. In some embodiments, the JAK is JAK3.

The compounds of the invention can be selective. By “selective” is meantthat the compound binds to or inhibits a JAK with greater affinity orpotency, respectively, compared to at least one other JAK. In someembodiments, the compounds of the invention are selective inhibitors ofJAK1 or JAK2 over JAK3 and/or TYK2. In some embodiments, the compoundsof the invention are selective inhibitors of JAK2 (e.g., over JAK1, JAK3and TYK2). Without wishing to be bound by theory, because inhibitors ofJAK3 can lead to immunosuppressive effects, a compound which isselective for JAK2 over JAK3 and which is useful in the treatment ofcancer (such as multiple myeloma, for example) can offer the additionaladvantage of having fewer immunosuppressive side effects. Selectivitycan be at least about 5-fold, 10-fold, at least about 20-fold, at leastabout 50-fold, at least about 100-fold, at least about 200-fold, atleast about 500-fold or at least about 1000-fold. Selectivity can bemeasured by methods routine in the art. In some embodiments, selectivitycan be tested at the Km of each enzyme. In some embodiments, selectivityof compounds of the invention for JAK2 over JAK3 can be determined bythe cellular ATP concentration.

Another aspect of the present invention pertains to methods of treatinga JAK-associated disease or disorder in an individual (e.g., patient) byadministering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of the presentinvention or a pharmaceutical composition thereof. A JAK-associateddisease can include any disease, disorder or condition that is directlyor indirectly linked to expression or activity of the JAK, includingoverexpression and/or abnormal activity levels. A JAK-associated diseasecan also include any disease, disorder or condition that can beprevented, ameliorated, or cured by modulating JAK activity.

Examples of JAK-associated diseases include diseases involving theimmune system including, for example, organ transplant rejection (e.g.,allograft rejection and graft versus host disease).

Further examples of JAK-associated diseases include autoimmune diseasessuch as multiple sclerosis, rheumatoid arthritis, juvenile arthritis,type I diabetes, lupus, psoriasis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulinnephropathies, autoimmune thyroid disorders, and the like. In someembodiments, the autoimmune disease is an autoimmune bullous skindisorder such as pemphigus vulgaris (PV) or bullous pemphigoid (BP).

Further examples of JAK-associated diseases include allergic conditionssuch as asthma, food allergies, atopic dermatitis and rhinitis. Furtherexamples of JAK-associated diseases include viral diseases such asEpstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1,Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV).

Further examples of JAK-associated diseases or conditions include skindisorders such as psoriasis (for example, psoriasis vulgaris), atopicdermatitis, skin rash, skin irritation, skin sensitization (e.g.,contact dermatitis or allergic contact dermatitis). For example, certainsubstances including some pharmaceuticals when topically applied cancause skin sensitization. In some embodiments, co-administration orsequential administration of at least one JAK inhibitor of the inventiontogether with the agent causing unwanted sensitization can be helpful intreating such unwanted sensitization or dermatitis. In some embodiments,the skin disorder is treated by topical administration of at least oneJAK inhibitor of the invention.

In further embodiments, the JAK-associated disease is cancer includingthose characterized by solid tumors (e.g., prostate cancer, renalcancer, hepatic cancer, pancreatic cancer, gastric cancer, breastcancer, lung cancer, cancers of the head and neck, thyroid cancer,glioblastoma, Kaposi's sarcoma, Castleman's disease, melanoma etc.),hematological cancers (e.g., lymphoma, leukemia such as acutelymphoblastic leukemia, or multiple myeloma), and skin cancer such ascutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Examplecutaneous T-cell lymphomas include Sezary syndrome and mycosisfungoides.

JAK-associated diseases can further include those characterized byexpression of a mutant JAK2 such as those having at least one mutationin the pseudo-kinase domain (e.g., JAK2V617F).

JAK-associated diseases can further include myeloproliferative disorders(MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET),myeloid metaplasia with myelofibrosis (MMM), chronic myelogenousleukemia (CML), chronic myelomonocytic leukemia (CMML),hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), andthe like.

Further JAK-associated diseases include inflammation and inflammatorydiseases. Example inflammatory diseases include inflammatory diseases ofthe eye (e.g., iritis, uveitis, scleritis, conjunctivitis, or relateddisease), inflammatory diseases of the respiratory tract (e.g., theupper respiratory tract including the nose and sinuses such as rhinitisor sinusitis or the lower respiratory tract including bronchitis,chronic obstructive pulmonary disease, and the like), inflammatorymyopathy such as myocarditis, and other inflammatory diseases.

The JAK inhibitors described herein can further be used to treatischemia reperfusion injuries or a disease or condition related to aninflammatory ischemic event such as stroke or cardiac arrest. The JAKinhibitors described herein can further be used to treat anorexia,cachexia, or fatigue such as that resulting from or associated withcancer. The JAK inhibitors described herein can further be used to treatrestenosis, sclerodermitis, or fibrosis. The JAK inhibitors describedherein can further be used to treat conditions associated with hypoxiaor astrogliosis such as, for example, diabetic retinopathy, cancer, orneurodegeneration. See, e.g., Dudley, A. C. et al. Biochem. J. 2005,390(Pt 2):427-36 and Sriram, K. et al. J. Biol. Chem. 2004,279(19):19936-47. Epub 2004 Mar. 2.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a JAK with a compound of the invention includesthe administration of a compound of the present invention to anindividual or patient, such as a human, having a JAK, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the JAK.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes one or more of the following:

(1) preventing the disease; for example, preventing a disease, conditionor disorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and

(3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology).

Combination Therapies

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, RAF and FAK kinaseinhibitors such as, for example, those described in WO 2006/056399, orother agents can be used in combination with the compounds of thepresent invention for treatment of JAK-associated diseases, disorders orconditions. The one or more additional pharmaceutical agents can beadministered to a patient simultaneously or sequentially.

Example chemotherapeutic include proteosome inhibitors (e.g.,bortezomib), thalidomide, revlimid, and DNA-damaging agents such asmelphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include coriticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include the compounds, and pharmaceuticallyacceptable salts thereof, of the genera and species disclosed in U.S.Pat. No. 5,521,184, WO 04/005281, EP2005/009967, EP2005/010408, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 03/037347, WO03/099771, and WO 04/046120.

Example suitable RAF inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO05/028444.

Example suitable FAK inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 04/080980, WO04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402.

In some embodiments, one or more JAK inhibitors of the invention can beused in combination with a chemotherapeutic in the treatment of cancer,such as multiple myeloma, and may improve the treatment response ascompared to the response to the chemotherapeutic agent alone, withoutexacerbation of its toxic effects. Examples of additional pharmaceuticalagents used in the treatment of multiple myeloma, for example, caninclude, without limitation, melphalan, melphalan plus prednisone [MP],doxorubicin, dexamethasone, and Velcade (bortezomib). Further additionalagents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3,RAF and FAK kinase inhibitors. Additive or synergistic effects aredesirable outcomes of combining a JAK inhibitor of the present inventionwith an additional agent. Furthermore, resistance of multiple myelomacells to agents such as dexamethasone may be reversible upon treatmentwith a JAK inhibitor of the present invention. The agents can becombined with the present compounds in a single or continuous dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with at least one JAK inhibitorwhere the dexamethasone is administered intermittently as opposed tocontinuously.

In some further embodiments, combinations of one or more JAK inhibitorsof the invention with other therapeutic agents can be administered to apatient prior to, during, and/or after a bone marrow transplant or stemcell transplant.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.Coated condoms, gloves and the like may also be useful.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers (excipients). In making the compositions of the invention, theactive ingredient is typically mixed with an excipient, diluted by anexcipient or enclosed within such a carrier in the form of, for example,a capsule, sachet, paper, or other container. When the excipient servesas a diluent, it can be a solid, semi-solid, or liquid material, whichacts as a vehicle, carrier or medium for the active ingredient. Thus,the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, suppositories, sterile injectablesolutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted hereinabove.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating JAK in tissue samples,including human, and for identifying JAK ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes JAKassays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro metalloprotease labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a JAK by monitoring its concentrationvariation when contacting with the JAK, through tracking of thelabeling. For example, a test compound (labeled) can be evaluated forits ability to reduce binding of another compound which is known to bindto a JAK (i.e., standard compound). Accordingly, the ability of a testcompound to compete with the standard compound for binding to the JAKdirectly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of JAK-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to be JAKinhibitors according to at least one assay described herein.

EXAMPLES Example 1:3-[3-Methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]benzonitrile

Step 1. 1H-Pyrrolo[2,3-b]pyridine 7-oxide

To a solution of 1H-pyrrolo[2,3-b]pyridine (4.90 g, 0.0415 mol) in ethylacetate (41 mL, 0.42 mol) was added a solution of meta-chloroperbenzoicacid (MCPBA; 9.3 g, 0.054 mol) in ethyl acetate (27 mL, 0.28 mol) at 0°C. The reaction mixture was solidified when ˜20 mL solution of MCPBA wasadded. An additional ˜10 mL of ethyl acetate was added so that asolution resulted. The reaction mixture was allowed to warm to roomtemperature (rt) and stirred overnight, then was cooled at 0° C.,filtered and washed with ethyl acetate three times to give 10.94 g wetsolid. The wet solid (8.45 g) was then suspended in water (35 mL), andto the suspension was added 13 mL of sat. Na₂CO₃ dropwise, and theresulting mixture was stirred at room temperature overnight. The mixturewas then cooled at 0° C., filtered and washed with water (×4) to give3.55 g of pale purple solid which was dried at 40° C. overnight to givethe desired product (2.47 g, 44.4% yield).

¹H NMR (400 MHz, CD₃OD): δ 8.2 (1H, d); 7.95 (1H, d); 7.5 (1H, d); 7.2(1H, m); 6.65 (1H, d). MS (M+H)⁺: 136.

Step 2. 4-Chloro-1H-pyrrolo[2,3-b]pyridine

To a pink solution of 1H-pyrrolo[2,3-b]pyridine 7-oxide (2.47 g, 0.0184mol) in dimethylformamide (DMF) (13.3 mL, 0.172 mol) was addedmethanesulfonyl chloride (4.0 mL, 0.052 mol) at 50° C., and the pinkcolor changed to orange. The reaction mixture was heated at 73° C. for 2h, then cooled to 40° C. Water (35 mL) was added, and the resultingsuspension was cooled at 0° C. NaOH was added to adjust the pH of themixture to about 7. The mixture was filtered and washed with water (×3)to give 3.8 g of a wet pale orange solid that was dried at 40° C.overnight to give the product (2.35 g, 82.2% yield).

¹H NMR (400 MHz, CDCl₃): δ 10.8 (1H, br); 8.21 (1H, d); 7.41 (1H, d);7.18 (1H, d); 6.61 (1H, d). MS (M+H)⁺: 153.

Step 3. 4-(4-Bromo-3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine

A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol)and 4-bromo-3-methyl-1H-pyrazole (0.10 g, 0.00066 mol) was heated at130° C. overnight. The reaction mixture then was subjected to columnchromatography (eluting with 5% MeOH/DCM, 0.5% NH₄OH, on silica gel) togive 80 mg pale yellow solid which was triturated with MeOH (1.5 mL) toyield the product as a pale yellow solid (44 mg, 44% yield).

¹H NMR (400 MHz, CD₃OD): δ 8.32 (1H, s); 8.25 (1H, d); 7.6 (1H, s); 7.45(1H, d); 7.37 (1H, d); 6.96 (1H, d); 2.4 (3H, s). MS (M+H)⁺: 276.

Step 4.3-[3-Methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]benzonitrile

A mixture of4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.032 g,0.00012 mol), (3-cyanophenyl)boronic acid (0.027 g, 0.00018 mol), sodiumcarbonate (0.032 g, 0.00030 mol) andtetrakis(triphenylphosphine)palladium(0) (7.0 mg, 0.0000060 mol) in1,2-dimethoxyethane (0.3 mL, 0.003 mol) and water (0.3 mL, 0.02 mol) washeated at 130° C. (a liquid resulted, but with two layers) for 4 h. Thereaction mixture then was cooled to room temperature (rt), filtered andwas washed with water (×2) and dimethyl ether (DME) (×2) to give theproduct as a pale orange solid (15 mg, 44% yield).

¹H NMR (400 MHz, CD₃OD): δ 8.57 (1H, s); 8.31 (1H, d); 7.8 (2H, m); 7.75(2H, m); 7.55 (1H, s); 7.45 (2H, m); 7.01 (1H, d); 2.6 (3H, s). MS(M+H)⁺: 299.

Example 2:(2E)-3-[3-Methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]acrylonitriletrifluoroacetate salt

Step 1. 4-Bromo-1H-pyrrolo[2,3-b]pyridine

To a solution of 1H-pyrrolo[2,3-b]pyridine 7-oxide (8.0 g, 0.060 mol),prepared by the procedure outlined in Example 1, Step 1 in DMF (100 mL,1 mol) was added methanesulphonic anhydride (20.8 g, 0.119 mol, in fourportions) at 0° C. The mixture was stirred at 0° C. for an additional 20min followed by an addition of tetramethylammonium bromide (23.0 g,0.149 mol). The resulting mixture was stirred overnight. Water (0.1 μL)was added, and a slight exotherm was observed. A solution of sodiumhydroxide in water (12.5 M, 12 mL) was added to adjust the pH of themixture to about 8, followed by an addition of ˜0.25 μL of water. Theresulting mixture was stirred for additional 2 h then filtered. Thesolid obtained was washed with water ×3 to give 6.72 g of a reddishsolid which was dried at 50° C. over a weekend to give the product (5.75g, 49% yield).

¹H NMR (400 MHz, CDCl₃): δ10.8 (1H, br); 8.2 (1H, d); 7.41 (1H, d); 7.19(1H, d); 6.61 (1H, d). MS (M+H)⁺: 196.

Step 2.4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (6.2 g, 0.031 mol)and [(3-(trimethylsilyl)ethoxy]methyl chloride (6.7 mL, 0.038 mol) inDMF (62 mL, 0.80 mol) was added sodium hydride (1.5 g, 0.038 mol) at 0°C., and the resulting solution turned opaque. The mixture was stirredfor additional 4 h, then diluted with methyl tert-butyl ether (MTBE).The organic layer was separated and washed with water (×2) and brineaqueous solution successively. The organic phase was dried andconcentrated in vacuo to give 14.1 g of a product as a pale orange oil.The oil was purified by column chromatography eluting with 5-20% ethylacetate/hexanes to give the purified product as a colorless oil (9.66 g,94% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.2 (1H, d); 7.49 (1H, d); 7.19 (1H, d); 6.62(1H, d); 5.78 (2H, s); 3.6 (2H, t); 0.98 (2H, t); 0.0 (9H, s). MS(M+H)⁺: 326.

Step 3.(2E)-3-[3-Methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-H-pyrazol-4-yl]acrylonitrile

A solution of 2-propenenitrile (0.043 mL, 0.00065 mol),bis(triphenylphosphine)palladium(II) chloride (0.0091 g, 0.000013 mol),4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.036 g,0.00013 mol), and tetraethylamine (TEA) (0.15 mL, 0.0011 mol) in DMF(0.15 mL, 0.0019 mol) was microwaved at 120° C. for 2 h. The solutionwas then diluted with ethyl acetate and washed with water (×2) and brinesuccessively. The organic phase was dried and concentrated in vacuo togive 62 mg of the product as an orange solid. The orange solid waspurified by prep-LCMS to give 12 mg of an off-white solid as atrifluoroacetic acid (TFA) salt which was triturated with MTBE (1 mL) toprovide the purified product as a pale green solid. (dried at 60° C. for4 h, 9 mg, 28% yield).

¹H NMR (400 MHz, CD₃OD): 2:1 of trans: cis isomers. For trans: δ 8.95(NH, 1H, s); 7.75 (olefin, 1H, d); 6.1 (olefin, 1H, d); 2.45 (Me, 3H,s). MS (M+H)⁺: 249.

Example 3:3-[3-Methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]propanenitrile,trifluoroacetate salt

A mixture of(2E)-3-[3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]acrylonitrile,TFA salt, (0.0050 g, 0.000020 mol, prepared according to Example 2) andpalladium (5.8 mg, 0.0000054 mol) in methanol (1 mL, 0.02 mol) and1,2-dichloroethane (1 mL, 0.01 mol) was degassed and then was stirredunder an atmosphere of hydrogen for 3 h. The reaction mixture then wasfiltered and the filtrate was concentrated in vacuo to give 8 mg of theproduct as an off-white solid. The crude material was purified byprep-LCMS to give 5.1 mg of a white solid as a TFA salt which wastriturated with MTB (1 mL) to give the product as a white solid (1.7 mg,34% yield).

¹H NMR (400 MHz, CD₃OD): δ 8.52 (1H, s); 8.35 (1H, d); 7.72 (1H, d); 7.6(1H, s); 7.38 (1H, d); 6.96 (1H, d); 2.7-2.9 (4H, m); 2.4 (3H, s). MS(M+H)⁺: 251.

Example 13: 4-(4-Phenyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridine

A melt of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) in4-phenyl-1H-imidazole (0.24 g, 0.0016 mol) was heated at 200° C.overnight. The reaction was partitioned between ethyl acetate andsaturated NaHCO₃, separated and the organic phase was washed with brine.The organic layer was then dried and evaporated to give 250 mg of anorange oil. The oil was chromatographed with 7% MeOH/DCM, 0.7% NH₄OH,sample in solvent system. Collected 74 mg of the product as an orangeglass. The glass was triturated with hot DCE (1.5 mL) to give 51 mg of abrown solid which was dried at 60° C. for 4 h to afford the desiredproduct (50 mg, 59 yield).

¹H NMR (400 MHz, dimethylsulxoxide (DMSO)): δ 12.5 (1H, s); 8.5 (1H, s);8.4 (1H, s); 8.38 (1H, d); 7.8 (2H, m); 7.62 (1H, d); 7.4 (3H, m); 7.3(1H, m); 6.81 (1H, d). MS (M+H)⁺: 260

Example 14:[3-Methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-piperidin-1-yl-methanone

Step 1.3-Methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazole-4-carboxylicacid

To a −70° C. solution of4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine(0.107 g, 0.000263 mol) in THF (1 mL, 0.01 mol), and n-butyllithium inhexane (0.23 mL of 1.6M), 0.5 g of CO₂ solid was added. After 15 min,the reaction was quenched with NH₄Cl. Ethyl acetate and water wereadded. The organic phase was washed with brine, and was evaporated togive 84 mg of an off-white glass/solid. The solid was chromatographedwith 50% ethyl acetate/hexanes, 0.5% AcOH, sample on silica gel to give40 mg of a purified product as a white solid (37% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.5 (1H, d); 7.45 (1H, d); 7.25 (1H, d); 7.02(1H, s); 6.6 (1H, d); 5.75 (2H, s); 3.6 (2H, t); 2.48 (3H, s); 0.98 (3H,t); 0.0 (9H, s). MS (M+H)⁺: 372.

Step 2.4-[3-Methyl-4-(piperidin-1-ylcarbonyl)-1H-pyrazol-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

A solution of3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazole-4-carboxylicacid (0.040 g, 0.00011 mol) (1:1 of AcOH) and N,N-carbonyldiimidazole(0.035 g, 0.00021 mol) in THF (1 mL, 0.01 mol) was stirred for 1.2 h,after which time piperidine (32 L, 0.00032 mol) was added. After another2 h, another portion of piperidine (15 μL) was added and the resultingmixture was stirred overnight. The reaction mixture was then partitionedbetween ethyl acetate and water, and washed sequentially with sat.NaHCO₃ and brine. The organic phase was dried and evaporated to give 49mg of the crude product as an orange oil/glass. The crude product waschromatographed with 75-100% ethyl acetate/hexanes, sample in DCM.Collected 25 mg of the purified product as a colorless glass/oil (50%yield).

¹H NMR (400 MHz, CDCl₃): δ 8.45 (1H, d); 8.23 (1H, s); 7.5 (1H, d); 7.4(1H, d); 7.05 (1H, d); 5.8 (2H, s); 3.7 (4H, br); 3.6 (2H, t); 2.55 (3H,s); 1.7 (6H, br); 1.0 (3H, t); 0.0 (9H, s). MS (M+H)⁺: 439.

Step 3.3-Methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl-piperidin-1-yl-methanone

A solution of4-[3-methyl-4-(piperidin-1-ylcarbonyl)-1H-pyrazol-1-yl]-1-[2-(trimethylsilyl)-ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.025 g, 0.000057 mol) in TFA (1 mL, 0.01 mol) was stirred for 1.5 h.The reaction mixture was then concentrated and partitioned between DCMand sat. NaHCO₃×2, and brine. The organic layer was then dried andconcentrated to give 28 mg of the product as a white foam. The foam wasdissolved in methanol (1 mL, 0.02 mol) and treated with ammoniumhydroxide in water (8.0M, 1 mL) for 1.5 h. The reaction was concentratedusing a rotary evaporator to give 24 mg of a pale yellow glass. Theglass was triturated with methyl t-butyl ether (MTBE) to give 13 mg of awhite solid which was dried at rt over a weekend. A total of 8 mg of theproduct was obtained after drying (45% yield).

¹H NMR (400 MHz, CDCl₃): δ 9.7 (1H, s); 8.4 (1H, d); 8.2 (1H, s); 7.42(1H, d); 7.4 (1H, d); 6.99 (1H, d); 3.4-3.8 (4H, br); 2.47 (3H, s);1.5-1.8 (6H, br). MS (M+H)⁺: 309.

Example 15:[3-Methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-ylmethyl]-phenyl-amine

Step 1.3-Methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazole-4-carbaldehyde

To a −70° C. solution of4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine(0.25 g, 0.00061 mol) in THF (2 mL, 0.03 mol), 1.6 M n-butyllithium inhexane (0.54 mL). After 10 min, DMF (120 μL, 0.0015 mol) was added. Thereaction was allowed to warm to rt and stirred overnight. The reactionwas then quenched with NH₄Cl. Ethyl acetate/water was added. The organicphase was separated and washed with brine, then dried and concentratedto give 180 mg of an orange oil. The crude product was chromatographedwith 25% ethyl acetate/hexanes, sample in DCM. Collected 40 mg of a paleyellow oil (18% yield).

¹H NMR (400 MHz, CDCl₃): δ 10.15 (1H, s); 8.7 (1H, s); 8.47 (1H, d);7.58 (1H, d); 7.5 (1H, d); 7.05 (1H, d); 5.8 (2H, s); 3.63 (2H, t); 2.7(3H, s); 0.98 (3H, t); 0.0 (9H, s). MS (M+H)⁺: 356.

Step 2.N-[3-Methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]methylaniline

A solution of3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazole-4-carbaldehyde(0.025 g, 0.000070 mol) and aniline (1M in DCM, 0.070 mL), in DCM (1 mL,0.02 mol) was stirred for 1 min. Acetic acid (20 μL, 0.0004 mol),aniline (1M in DCM, 140 L) and sodium triacetoxyborohydride (0.022 g,0.00010 mol) were added. The reaction was stirred overnight andpartitioned between DCM and sat. NaHCO₃, washed with brine. The organicphase was dried and evaporated to give 21 mg of a product as a paleorange glass (70% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.4 (1H, d); 8.15 (1H, s); 7.65 (1H, d); 7.35(3H, m); 7.09 (1H, d); 6.82 (1H, m); 6.89 (2H, m); 5.8 (2H, s); 4.35(2H, s); 3.6 (2H, t); 2.5 (3H, s); 0.99 (3H, t); 0.0 (9H, s). MS (M+H)⁺:433.

Step 3.[3-Methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-ylmethyl]-phenyl-amine

Deprotection ofN-[3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]methylanilinewas carried out according to the procedures of Example 14, Step 3 togive the desired product (58% yield).

¹H NMR (400 MHz, CDCl₃): δ 9.9 (1H, s); 8.38 (1H, d); 8.1 (1H, s); 7.4(1H, d); 7.35 (1H, d); 7.3 (2H, m); 7.0 (1H, d); 6.79 (1H, m); 6.77 (2H,m); 4.25 (2H, s); 3.81 (1H, s); 2.41 (3H, s). MS (M+H)⁺: 303.

Example 25:3-[3-Methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-cyclohexanol

Step 1.3-Ethoxy-1-[3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]cyclohex-2-en-1-ol

To a −75° C. solution of4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine(0.11 g, 0.00027 mol) in THF (1.5 mL, 0.018 mol) was added 1.6 Mn-butyllithium in hexane (0.22 mL). The reaction mixture turned darkorange. After ˜10 min, 1.0 M magnesium dibromide in ether (0.35 mL) wasadded. After another 50 min, a solution of 3-ethoxy-2-cyclohexen-1-one(41.5 μL, 0.000308 mol) in THF (˜0.3 mL) was added. The resultingmixture was warmed to −40° C. over ˜1 h and quenched with NH₄Cl. Thenethyl acetate/water was added. The organic phase was washed with brine,and concentrated to give 145 mg of an orange oil. The crude product waschromatographed with 0-50% ethyl acetate/hexane gradient, sample in DCM.Collected 35 mg of the produce as an oil (30% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.49 (1H, d); 8.38 (1H, s); 7.55 (1H, d); 7.4(1H, d); 7.1 (1H, d); 6.0 (2H, s); 3.6 (2H, t); 2.81 (2H, m); 2.62 (3H,s); 2.58 (2H, m); 2.27 (2H, m); 1.0 (3H, t); 0.0 (9H, s). MS (M+H)⁺:422.

Step 2.3-[3-Methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]cyclohexanol

A mixture of3-[3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]cyclohex-2-en-1-one(0.019 g, 0.000045 mol) and palladium on carbon (Pd/C) (0.018 g,0.000017 mol) in methanol (2 mL, 0.05 mol) was degassed and was stirredunder a hydrogen atmosphere overnight. An additional 48 mg of 10% Pd/Cwas added and stirred under a hydrogen atmosphere for 8 h. The palladiumwas filtered and the filtrate was stirred with sodium tetrahydroborate(0.032 g, 0.00084 mol) for 5 h. The reaction was purified by prep-HPLCto give 5 mg of the desired product. MS (M+H)⁺: 426.

Step 3.3-[3-Methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-cyclohexanol

Deprotection of3-[3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]cyclohexanolwas carried out according to the procedures of Example 14, Step 3 togive the desired product (40% yield).

¹H NMR (400 MHz, CDCl₃): δ 9.72 (1H, s); 8.35 (1H, d); 7.95 (1H, s);7.41 (1H, d); 7.35 (1H, d); 7.02 (1H, d); 3.78 (1H, m); 2.6 (1H, m); 2.4(3H, s); 1.2-2.4 (8H, m). MS (M+H)⁺: 296.

Example 40:4-[1-(3-Methoxy-1-methyl-propyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine

Step 1.4-[1-(3-Methoxy-1-methylpropyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine

To a 0° C. solution of3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol(the alcohol was made by DIBAL reduction of the ester in Example 58)(0.056 g, 0.00014 mol)) in DMF (1 mL, 0.01 mol), was added sodiumhydride (0.0107 g, 0.000268 mol). After 5 min, methyl iodide (18 μL,0.00029 mol) was added and the resulting mixture was stirred over aweekend. The mixture was then partitioned between ethyl acetate andwater, separated and the organic phase was washed with brine. Theorganic phase was concentrated to give a pale orange oil.

¹H NMR (400 MHz, CDCl₃): δ 8.4 (1H, d); 8.3 (1H, s); 8.0 (1H, s); 7.65(1H, d); 7.27 (1H, d); 6.8 (1H, d); 5.8 (2H, s); 4.7 (1H, m); 3.63 (2H,t); 3.2-3.4 (2H, m); 3.38 (3H, s); 2.1-2.3 (2H, m); 1.7 (3H, d); 1.0(2H, t); 0.0 (9H, s). MS (M+H)⁺: 400.

Step 2.4-[1-(3-Methoxy-1-methyl-propyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine

Deprotection of4-[1-(3-methoxy-1-methylpropyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)-ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridinewas carried out according to the procedures of Example 14, Step 3 togive the desired product (25% yield).

¹H NMR (400 MHz, CDCl₃): δ 10.0 (1H, s); 8.35 (1H, d); 8.18 (1H, s);7.95 (1H, s); 7.41 (1H, d); 7.21 (1H, d); 6.75 (1H, d); 4.63 (1H, m);3.15-3.4 (2H, m); 3.35 (3H, s); 2.21-2.05 (2H, m); 1.6 (3H, d). MS(M+H)⁺: 270.

Example 42:4-[1-(1-Methyl-3-pyrazol-1-yl-propyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine

Step 1.4-1-[1-Methyl-3-(1H-pyrazol-1-yl)propyl]-1H-pyrazol-4-yl-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

To a 0° C. solution of3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butylmethanesulfonate (prepared by mesylation of the alcohol as in Example59, Step 1) (0.055 g, 0.00012 mol) and 1H-pyrazole (0.025 g, 0.00036mol) in DMF (1 mL, 0.01 mol) was added sodium hydride (0.014 g, 0.00036mol). The resulting solution was stirred overnight and then partitionedbetween ethyl acetate and 0.1 N HCl, water. the organic phase wasseparated and washed with brine. The organic layer was then concentratedto give 49 mg of a pale orange glass (87% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.4 (1H, d); 8.18 (1H, s); 7.99 (1H, s); 7.6(1H, t); 7.5 (1H, d); 7.4 (1H, t); 7.27 (1H, d); 6.8 (1H, d); 6.3 (1H,m); 5.8 (2H, s); 4.2 (1H, m); 4.0-4.2 (2H, m); 3.61 (2H, t); 2.58 (2H,m); 1.65 (3H, d); 1.0 (2H, t); 0.0 (9H, s). MS (M+H)⁺: 436.

Step 2.4-[1-(1-Methyl-3-pyrazol-1-yl-propyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine

Deprotection of4-1-[1-methyl-3-(1H-pyrazol-1-yl)propyl]-1H-pyrazol-4-yl-1-[2-(trimethyl-silyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridinewas carried out according to the procedures of Example 14, Step 3 togive the desired product (38% yield).

¹H NMR (400 MHz, CDCl₃): δ 9.7 (1H, s); 8.38 (1H, d); 8.1 (1H, s); 7.7(1H, s); 7.59 (1H, t); 7.4 (1H, d); 7.35 (1H, t); 7.21 (1H, d); 6.75(1H, d); 6.25 (1H, m); 4.4 (1H, m); 3.9-4.15 (2H, m); 2.55 (2H, m); 1.63(3H, d). MS (M+H)⁺: 306.

The following compounds in Table 1 were made by methods analogous to theprocedures above as indicated. “Purification A” indicates that theproduct following deprotection was purified by preparative-HPLC underthe following conditions: C18 eluting with a gradient of MeCN/H₂Ocontaining 0.15% NH₄OH.

TABLE 1 Ex. MS No. Structure Name (M + H) Prep. Ex. No. 4

1-(1H-Pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazole-4-carboxylic acid ethylester 256 1 5

4-(3-Methyl-4-phenyl-pyrazol-1- yl)-1H-pyrrolo[2,3-b]pyridine 274 1 6

4-(3-Phenyl-pyrazol-1-yl)-1H- pyrrolo[2,3-b]pyridine 260 1 7

4-(4-Bromo-imidazol-1-yl)-1H- pyrrolo[2,3-b]pyridine 262 13 8

4-(4-Bromo-3-methyl-pyrazol-1- yl)-1H-pyrrolo[2,3-b]pyridine 262 1 9

3-[3-Methyl-1-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-4-yl]-benzonitrile 299 1 10

4-[3-Methyl-1-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-4-yl]-benzonitrile 299 1 16

4-[4-(3-Fluoro-phenyl)-3-methyl- pyrazol-1-yl]-1H-pyrrolo[2,3-b]pyridine 292 1 17

4-[4-(3,5-Bis-trifluoromethyl- phenyl)-3-methyl-pyrazol-1-yl]-1H-pyrrolo[2,3-b]pyridine 410 1 18

4-[4-(3,5-Difluoro-phenyl)-3- methyl-pyrazol-1-yl]-1H-pyrrolo[2,3-b]pyridine 310 1 19

{3-[3-Methyl-1-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-4-yl]-phenyl}-methanol 304 1 20

4-(3-Methyl-4-pyrimidin-5-yl- pyrazol-1-yl)-1H-pyrrolo[2,3-b]- pyridine276 1 21

4-[3-Methyl-4-(1-methyl-1H- indol-5-yl)-pyrazol-1-yl]-1H-pyrrolo[2,3-b]pyridine 327 1 22

4-(3-Methyl-4-thiophen-3-yl- pyrazol-1-yl)-1H-pyrrolo[2,3-b]- pyridine280 1 23

N,N-Dimethyl-4-[3-methyl-1- (1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]- benzenesulfonamide 381 1 24

N-{4-[3-Methyl-1-(1H- pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-phenyl}-acetamide 331 1 26

3-tert-Butyl-1-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazole-4-carbonitrile 265 1 27

4-Bromo-1-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-1H-pyrazole-3- carbonitrile287 1 28

4-(3-Cyano-phenyl)-1-(1H- pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazole-3-carbonitrile 310 1 29

3-[1-(1H-Pyrrolo[2,3-b]pyridin-4- yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-propan-1-ol 254 1 30

3-[3-Methyl-1-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-4-yl]-prop-2-en-1-ol 310 1 31

2-[4-Bromo-1-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-3-yl]-isoindole-1,3-dione 408 1 32

4-[4-(2,6-Dimethyl-phenyl)-3- methyl-pyrazol-1-yl]-1H-pyrrolo[2,3-b]pyridine 302 1 33

3-[3-Amino-1-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-4-yl]-benzonitrile 300 1 34

3-[3-Benzylamino-1-(1H- pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-benzonitrile 390 1, 15 35

N-[4-(3-Cyano-phenyl)-1-(1H- pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-acetamide 342 1, 14 36

3-[4-(1H-Pyrrolo[2,3-b]pyridin-4- yl)-pyrazol-1-yl]-propan-1-ol 242 58Purification A 37

3-[4-(1H-Pyrrolo[2,3-b]pyridin-4- yl)-pyrazol-1-yl]-butan-1-ol 256 58Purification A 38

4-[4-(1H-Pyrrolo[2,3-b]pyridin-4- yl)pyrazol-1-yl]-pentanenitrile 265 59Purification A 39

4-[4-(1H-Pyrrolo[2,3-b]pyridin-4- yl)-pyrazol-1-yl]-pentanoic acid amide283 60 Purification A 41

4-[1-(3-Imidazol-1-yl-1-methyl- propyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine 306 42 43

4-Cyclopentyl-4-[4-(1H- pyrrolo[2,3-b]pyridin-4-yl)-pyrazol-1-yl]-butyronitrile 319 59 Purification A 44

4-Cyclopentyl-4-[4-(1H- pyrrolo[2,3-b]pyridin-4-yl)-pyrazol-1-yl]-butyramide 337 60 Purification A 45

3-Cyclopropyl-3-[4-(1H- pyrrolo[2,3-d]pyrimidin-4-yl)-pyrazol-1-yl]-propionitrile 278 61 Purification A

Example 46:4-(2-tert-Butyl-1-methyl-1H-imidazol-4-yl)-1H-pyrrolo[2,3-b]pyridinetrifluoroacetate salt

Step 1.4-(2-tert-butyl-1H-imidazol-5-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

To a solution of trimethylacetic acid (0.169 mL, 0.00147 mol) in ethanol(6 mL, 0.1 mol) was added cesium carbonate (0.24 g, 0.00073 mol), andthe resulting mixture was stirred for 2 hours. The solvent was removedin vacuo to afford cesium pivalate.

To a solution of2-chloro-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethanone(prepared, e.g., as in Ex. 50, Step 1) (0.054 g, 0.00017 mol) in DMF(1.8 mL, 0.023 mol) was added cesium pivalate (0.0389 g, 0.000166 mol)and the reaction was stirred at room temperature for 16 hours. Ammoniumacetate (0.45 g, 0.0058 mol) was added, and the reaction was heated inthe microwave to 170° C. for 5 minutes. Water was added and the productwas extracted with MTBE. The combined organic extracts were dried oversodium sulfate, then filtered and concentrated. The crude residue waspurified by flash column chromatography (2.5% MeOH/DCM) to yield4-(2-tert-butyl-1H-imidazol-5-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(32 mg, 52%). ¹H NMR (400 MHz, CDCl₃): δ □8.31 (d, 1H), 7.50 (s, 1H),7.40 (d, 1H), 7.37 (d, 1H), 6.94 (d, 1H), 5.69 (s, 2H), 3.52 (dd, 2H),1.46 (s, 9H), 0.90 (dd, 2H), −0.08 (s, 9H); MS(ES):371 (M+1).

Step 2.4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo-[2,3-b]pyridine

To a mixture of4-(2-tert-butyl-1H-imidazol-5-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.019 g, 0.000051 mol) and potassium carbonate (0.15 g, 0.0011 mol) inDMF (3 mL, 0.04 mol) was added methyl iodide (0.01 mL, 0.00015 mol) intwo portions over 48 hours. Water was then added and the product wasextracted with MTBE. The combined extracts were dried with sodiumsulfate, filtered, and concentrated in vacuo, then purified by silicagel chromatography (20% ethyl acetate/hexanes) to afford4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(10 mg, 51%).

¹H NMR (400 MHz, CDCl₃): δ □8.37 (d, 1H), 7.54 (d, 1H), 7.44-7.22 (m,2H), 7.19 (d, 1H), 5.78 (s, 2H), 3.93 (s, 3H), 3.60 (dd, 2H), 1.61 (s,9H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):385 (M+1).

Step 3

A solution of4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1-[2-(trimethylsilyl)-ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine(0.010 g, 0.000026 mol) in TFA (3 mL, 0.04 mol) was stirred for 2 hours.Then the excess TFA was evaporated and the residue was stirred inmethanol (3 mL, 0.07 mol) and NH₄OH (1 mL) for 16 hours. The solventswere removed and the product was purified by preparative-HPLC (C18eluting with a gradient of ACN/H₂O containing 0.1% TFA) to afford4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1H-pyrrolo[2,3-b]pyridine,trifluoroacetate salt (9 mg, 90%).

¹H NMR (400 MHz, d₆-DMSO): δ □12.24 (s, 1H), 8.38 (br s, 1H), 8.24 (s,1H), 7.70-7.63 (m, 2H), 7.08 (br s, 1H), 2.55 (s, 3H), 1.51 (s, 9H);MS(ES):255 (M+1).

Additional analogs were prepared as shown in Table 2 using analogousprocedures to those described in Example 46 with different startingmaterials such as alternative carboxylic acids in Step 1. When theanalogs were obtained as the free base, the product was obtained bypreparative-HPLC (C18 eluting with a gradient of ACN/H₂O containing0.15% NH₄OH). The results are summarized in Table 2 according to thefollowing structure:

TABLE 2

(MS) (ES) Ex. (M + No. Name —(Y)_(n)—Z 1) 47 4-(2-phenyl-1H-imidazol-5-yl)-1H- pyrrolo[2,3-b]pyridine

261 48 4-(2-benzyl-1H-imidazol- 5-yl)- 1H-pyrrolo[2,3-b]pyridinetrifluoroacetate salt

275 49 4-[2-(1-phenylethyl)-1H- imidazol-5-yl]-1H-pyrrolo[2,3-b]pyridine trifluoroacetate salt

289

Example 50: 4-(2-Phenyl-1,3-thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridinetrifluoroacetate salt

Step 1.2-Chloro-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethanone

To a solution of4-bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(2.05 g, 0.00626 mol) in THF (10 mL, 0.123 mol) at 0° C. was addeddropwise a solution of isopropylmagnesium chloride in ether (2.0 M, 9.4mL). The mixture was allowed to warm to room temperature and stirred for4 hours. This mixture was then transferred via cannula to a solution of2-chloro-N-methoxy-N-methylacetamide (2.84 g, 0.0207 mol) in THF (10ml). After 30 minutes reaction time, the solution was quenched by theaddition of saturated ammonium chloride aqueous solution. The productwas extracted with ethyl acetate, the combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude residue was purified by flash column chromatography (0-20% ethylacetate/hexanes) to afford2-chloro-1-(1-[2-(trimethylsilyl)-ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethanone(711 mg, 35%). ¹H NMR (400 MHz, CDCl₃): δ □8.56 (d, 1H), 7.66 (d, 1H),7.60 (d, 1H), 7.23 (d, 1H), 5.80 (s, 2H), 4.91 (s, 2H), 3.60 (dd, 2H),0.98 (dd, 2H), 0.01 (s, 9H); MS(ES):325 (M+1).

Step 2. 4-(2-Phenyl-1,3-thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridinetrifluoroacetate salt

A solution of2-chloro-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-ethanone(0.050 g, 0.00015 mol) and benzenecarbothioamide (0.031 g, 0.00022 mol)in ethanol (2 mL, 0.03 mol) was heated to reflux for 1 hour. The solventwas removed in vacuo. Ethyl acetate was added, and the resulting solidwas isolated by filtration. The crude solid was stirred with TFA for 1hour, then excess TFA was removed in vacuo. The crude residue was thenstirred with aq. NH₄OH and MeOH for 16 hours. The solvent was removedand the product was purified by preparative-HPLC (C18 eluting with agradient of ACN/H₂O containing 0.1% TFA) to afford4-(2-phenyl-1,3-thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine as thetrifluoroacetate salt (11 mg, 18%). ¹H NMR (400 MHz, d₆-DMSO): δ □12.01(s, 1H), 8.58 (s, 1H), 8.39 (br s, 1H), 8.13-8.07 (m, 2H), 7.81 (d, 1H),7.67-7.64 (m, 1H), 7.62-7.52 (m, 3H), 7.22 (d, 1H); MS(ES):278 (M+1).

Example 51:N-Methyl-N-propyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-thiazol-2-amine,trifluoroacetate salt

Step 1. N-Methyl-N-propylthiourea

N-Methyl-N-propylamine (0.501 mL, 0.00488 mol) was added to a solutionof 1,1′-thiocarbonyldiimidazole (0.957 g, 0.00537 mol) in THF (9 mL, 0.1mol), and the resulting solution was stirred for 16 hours. Theintermediate from the reaction mixture was isolated by silica gelchromatography (5% MeOH in DCM) and this intermediate was stirred withammonia (7M solution in MeOH) (6 mL) for 48 hours. The solvent wasremoved in vacuo. N-methyl-N-propylthiourea was obtained after flashcolumn chromatography (4% MeOH in DCM).

Step 2

A solution of2-chloro-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-ethanone(0.050 g, 0.00015 mol) and N-methyl-N-propylthiourea (0.030 g, 0.00022mol) in ethanol (2 mL, 0.03 mol) was heated to reflux for 2 hours. Then,the ethanol was removed in vacuo and the residue was dissolved in 2 mLTFA and stirred for 40 minutes. The excess TFA was removed in vacuo andthe residue was dissolved in 3 mL of MeOH. To this was added 0.5 mL ofNH₄OH and 100 L of ethylenediamine, and the resulting solution wasstirred for 16 hours. Solvent was removed, then water was added to givea white precipitate which was purified by preparative-HPLC (C18 elutingwith a gradient of ACN/H₂O containing 0.1% TFA) to affordN-methyl-N-propyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-thiazol-2-amineas the trifluoroacetate salt (39 mg, 67%). ¹H NMR (300 MHz, CD₃OD): δ□8.46-8.12 (br s, 1H), 7.92 (br s, 1H), 7.72 (s, 1H), 7.63 (d, 1H), 7.45(br s, 1H), 3.56 (t, 2H), 3.20 (s, 3H), 1.78 (dq, 2H), 1.00 (t, 3H);MS(ES):273 (M+1).

Additional aminothiazole analogs were prepared by procedures analogousto those described in Example 51, using different starting materialssuch as alternative thioureas in Step 2. In Examples 52 and 53, thewhite precipitate obtained by the procedure of Example 51 was isolatedby filtration, washed with water and dried under high vacuum to affordthe analogs as the free amine. The results are summarized in Table 3according to the following structure:

TABLE 3

Ex. MS (ES) No. Name R (M + 1) 52 N-phenyl-4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1,3-thiazol-2-amine

293 53 N-methyl-N-phenyl-4- (1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-thiazol- 2-amine

307

Example 54: 4-(2-Phenyl-1,3-thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridinetrifluoroacetate salt

Step 1. (2-Phenyl-1,3-thiazol-5-yl)boronic acid

To a solution of n-butyllithium in hexane (1.6 M, 2.1 mL) in ether (20mL) at −78° C., a solution of 2-phenyl-1,3-thiazole (449 mg, 0.00278mol) in ether (5 mL) was added dropwise. The mixture was stirred for onehour at −78° C. followed by the addition of boric acid trimethyl ester(0.949 mL, 0.00835 mol). The mixture was stirred at −78° C. for 15minutes, then was allowed to warm to room temperature and stirred for anadditional 40 minutes. Saturated NH₄Cl aqueous solution was added,followed by 1.0 N aqueous HCl. The acidified mixture was stirred for 15minutes, and the desired product was extracted with four portions of DCMcontaining 15% isopropanol. The combined organic extracts were driedover sodium sulfate and concentrated to give 566 mg of a white solidcontaining the desired (2-phenyl-1,3-thiazol-5-yl)boronic acid as amixture with 2-phenyl-1,3-thiazole. This mixture was used in Step 2without further purification. MS(ES):206 (M+1).

Step 2

To a mixture of (2-phenyl-1,3-thiazol-5-yl)boronic acid (75.0 mg,0.000366 mol) and4-bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (80mg, 0.000244 mol) in DMF (4 mL, 0.0516 mol) was added a solution ofpotassium carbonate (101 mg, 0.000732 mol) in water (1 mL, 0.0555 mol).The mixture was purged with a steady stream of nitrogen for 15 minutes.

Tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.000018 mol) was addedand the resulting mixture was heated to 125° C. for 30 minutes. Theproduct was purified by preparative-HPLC (C18 eluting with a gradient ofACN/H₂O containing 0.1% TFA) to afford 12 mg of a yellow solidcontaining the desired product as the major component. The mixture wasstirred in TFA (1 mL) for 1 hour. Then excess TFA was removed in vacuoand the resulting residue was stirred with 2 mL MeOH, 0.5 mL NH₄OH and100 μL ethylenediamine for 16 hours. The product was isolated bypreparative-HPLC (C18 eluting with a gradient of ACN/H₂O containing 0.1%TFA) to afford 4-(2-phenyl-1,3-thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridinetrifluoroacetate salt (5 mg, 5%). ¹H NMR (400 MHz, CD₃OD): δ □8.64 (s,1H), 8.34 (d, 1H), 8.10-8.04 (m, 2H), 7.73 (d, 1H), 7.71 (d, 1H),7.56-7.51 (m, 3H), 7.14 (d, 1H); MS(ES):278 (M+1).

Example 55: Ethyl2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoatetrifluoroacetate salt (55a) AND2-Methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoicacid (55b)

4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-H-pyrrolo[2,3-b]pyridine(60 mg, 0.00019 mol) was dissolved in DMF (1.5 mL), and the solution wascooled to 0° C. with a cold bath. Sodium hydride (15 mg, 0.00038 mol)was added. After stirring for 10 min, 2-bromo-2-methyl-propanoic acidethyl ester (42 μL, 0.00028 mol) was added. The cold bath was thenremoved and the reaction mixture was allowed to warm to room temperatureover 1 hour. The reaction mixture was quenched with saturated ammoniumchloride solution. More water was added, and the product was extractedwith MTBE. The combined extracts were dried over sodium sulfate,filtered and concentrated. The residue was dissolved in 2 mL TFA andstirred for 1 h. Then excess TFA was removed in vacuo and the resultingresidue was stirred in 2 mL EtOH containing 0.6 mL NH₄OH solution for 16hours. Volatiles were removed, and purification of the mixture wascarried out via preparative-HPLC (C18 eluting with a gradient of ACN/H₂Ocontaining 0.1% TFA) afforded ethyl2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoatetrifluoroacetate salt (13 mg, 17%): ¹H NMR (300 MHz, d₆-DMSO): δ □12.03(s, 1H), 8.67 (s, 1H), 8.31-8.19 (m, 2H), 7.59 (t, 1H), 7.48 (d, 1H),6.98 (br s, 1H), 4.10 (q, 2H), 1.84 (s, 6H), 1.12 (t, 3H); MS(ES):299(M+1) and2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoicacid (27 mg, 53%): ¹H NMR (300 MHz, d₆-DMSO): δ □12.04 (s, 1H), 8.64 (s,1H), 8.26 (s, 2H), 7.59 (br s, 1H), 7.48 (d, 1H), 6.99 (br s, 1H), 1.83(s, 6H); MS(ES):271 (M+H).

Example 56:2-Methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanamide

A mixture of2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoicacid (23 mg, 0.000085 mol) and N,N-carbonyldiimidazole (CDI) (21 mg,0.00013 mol) in 2 mL of DMF was stirred for 3 hours. An excess of solidNH₄Cl and TEA was added to the mixture and this was stirred for 3 hours.The majority of solvent was removed in vacuo, and the crude residue waspurified by preparative-HPLC (C18 eluting with a gradient of ACN/H₂Ocontaining 0.1% TFA) followed by re-purification via preparative-HPLC(C18 eluting with a gradient of ACN/H₂O containing 0.15% NH₄OH) toafford2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanamide(6 mg, 26%). ¹H NMR (400 MHz, d₆-DMSO): δ □11.63 (s, 1H), 8.44 (s, 1H),8.16 (s, 1H), 8.14 (s, 1H), 7.47 (t, 1H), 7.29 (d, 1H), 7.21 (s, 1H),6.93 (s, 1H), 6.80 (dd, 1H), 1.77 (s, 6H); MS(ES):270 (M+1).

Example 57: Ethyl3-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoatetrifluoroacetate salt

Step 1. Ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoate

4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(220 mg, 0.0006996 mol) and 3-methyl-2-butenoic acid ethyl ester (292μL, 0.00210 mol) were dissolved in DMF (10 mL). Cesium carbonate (912mg, 0.00280 mol) was added and the resulting mixture was stirred at roomtemperature for 3 hours. The reaction mixture was diluted with water,and the product was extracted with MTBE several times. The combinedextracts were dried over sodium sulfate and concentrated. The cruderesidue was purified by flash column chromatography (0-60%EtOAc/Hexanes) to afford ethyl3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoate(244 mg, 79%). ¹H NMR (300 MHz, CDCl₃): δ 8.37 (d, 1H), 8.11 (s, 1H),8.09 (s, 1H), 7.45 (d, 1H), 7.24 (d, 1H), 6.79 (d, 1H), 5.77 (s, 2H),4.10 (q, 2H), 3.62 (dd, 2H), 3.04 (s, 2H), 1.88 (s, 6H), 1.20 (t, 3H),0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):443 (M+1).

Step 2

Ethyl3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoate(20 mg, 0.0000452 mol) was stirred in 1 mL TFA for 1 hour. Then excessTFA was removed in vacuo. The residue was stirred for 16 hours in 2 mLMeOH containing 0.5 mL NH₄OH. Evaporation of the volatiles was followedby purification by preparative-HPLC (C18 eluting with a gradient ofACN/H₂O containing 0.1% TFA) to afford ethyl3-methyl-3-[4-(1H-pyrrolo[2,3-b]-pyridin-4-yl)-1H-pyrazol-1-yl]butanoate,trifluoroacetate salt (5 mg, 26%). ¹H NMR (400 MHz, d₆-DMSO): δ □12.19(s, 1H), 8.61 (br s, 1H), 8.34-8.22 (br m, 2H), 7.62 (br s, 1H), 7.51(br d, 1H), 7.02 (br s, 1H), 3.91 (q, 2H), 2.96 (s, 2H), 1.70 (s, 6H),1.02 (t, 3H); MS(ES):313 (M+1).

Example 58:3-Methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-oltrifluoroacetate salt

To a solution of ethyl3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridin-4-yl)-1H-pyrazol-1-yl]butanoate(213 mg, 0.000481 mol) in THF (5 mL, 0.0616 mol) at −78° C. was addeddiisobutylaluminum hydride in DCM (1.00 M, 1.1 mL) dropwise. Thereaction mixture was stirred for 3 hours during which time the reactionslowly warmed to −10° C. To the mixture at −10° C. was carefully addedK/Na tartrate tetrahydrate in water. The mixture was stirred for 2hours, then was extracted with three portions of ethyl acetate. Thecombined organic extracts were washed with two portions of water and oneportion of brine, then dried over sodium sulfate, filtered andconcentrated to afford3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol(185 mg, 96%), which was used without further purification. A portion ofthe alcohol so obtained (15 mg, 0.000037 mol) was stirred in TFA (1 mL)for 2 hours. The TFA was removed in vacuo and the residue was stirredwith 2 mL MeOH containing 0.5 mL NH₄OH for 16 hours. Volatiles wereremoved and the product was purified by preparative-HPLC (C18 elutingwith a gradient of ACN/H₂O containing 0.1% TFA) to afford3-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-olas the trifluoroacetate salt (8.0 mg, 57%). ¹H NMR (300 MHz, d₆-DMSO): δ□12.17 (s, 1H), 8.58 (br s, 1H), 8.32-8.22 (br m, 2H), 7.62 (br s, 1H),7.53 (br d, 1H), 7.03 (br s, 1H), 3.25 (t, 2H), 2.07 (t, 2H), 1.62 (s,6H); MS(ES):271 (M+1).

Example 59:4-Methyl-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitriletrifluoroacetate salt

Step 1. 4-Methyl-4-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrile

TEA (38.0 μL, 0.000273 mol) and methanesulfonyl chloride (21.1 μL,0.000273 mol) were added sequentially to a solution of3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol(prepared as in Example 58) (81 mg, 0.00020 mol) in DCM (4 mL, 0.05 mol)at 0° C. The reaction mixture was held at this temperature for 1.5hours, then was quenched by the addition of water. The reaction mixturewas extracted with DCM four times. The combined extracts were dried oversodium sulfate, filtered and concentrated to afford crude3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butylmethanesulfonate (87 mg). MS(ES):479 (M+1).

A mixture of3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butylmethanesulfonate (42 mg, 0.000088 mol) and potassium cyanide (46 mg,0.000702 mol) in DMF (1 mL) was heated in the microwave reactor for 30min at 125° C. followed by additional 30 min at 135° C. The mixture wasthen diluted with water, and the product was extracted with threeportions of MTBE. The combined extracts were dried over sodium sulfate,filtered and concentrated to give 61 mg of crude4-methyl-4-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo-[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrile,which was used without further purification. MS(ES):410 (M+1).

Step 2

4-Methyl-4-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrile(57 mg, 0.00014 mol) was stirred in DCM (4 ml) and TFA (1 mL) for 2hours. The solvents were removed in vacuo and the residue was stirred in2 mL MeOH containing 0.2 mL ethylenediamine for 16 hours. The volatileswere evaporated and the product was isolated from the reaction mixtureby preparative-HPLC (C18 eluting with a gradient of ACN/H₂O containing0.1% TFA) affording4-methyl-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrileas the trifluoroacetate salt (10 mg, 18%). ¹H NMR (400 MHz, d₆-DMSO): δ□12.09 (s, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 8.25 (d, 1H), 7.60 (t, 1H),7.48 (d, 1H), 7.00 (br s, 1H), 2.33-2.21 (m, 4H), 1.61 (s, 6H);MS(ES):280 (M+1).

Example 60:4-Methyl-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanamidetrifluoroacetate salt

The crude4-methyl-4-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrile(36 mg, 0.000088 mol, see preparation in Example 59), was stirred in TFA(2 mL) for 1 hour. The mixture was concentrated to remove excess TFA,and the resulting residue was stirred in 2 mL methanol containing 0.5 mLNH₄OH for 16 hours. The product was purified by preparative-HPLC (C18eluting with a gradient of ACN/H₂O containing 0.1% TFA) to afford4-methyl-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanamideas the trifluoroacetate salt (21 mg, 58%). ¹H NMR (400 MHz, d₆-DMSO): δ□12.18 (s, 1H), 8.60 (s, 1H), 8.33-8.21 (m, 2H), 7.62 (br s, 1H), 7.53(d, 1H), 7.22 (br s, 1H), 7.04 (br s, 1H), 6.71 (br s, 1H), 2.14-2.07(m, 2H), 1.86-1.79 (m, 2H), 1.58 (s, 6H); MS(ES):298 (M+1).

Example 61:(3S)-3-[4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanenitriletrifluoroacetate salt AND(3R)-3-[4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanenitriletrifluoroacetate salt

To a solution of4-(1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.050 g, 0.00016 mol) in ACN were added 2-butenenitrile (0.014 mL,0.00017 mol) and DBU (0.029 mL, 0.00020 mol). The resulting mixture wasstirred for 16 hours. Then the volatiles were evaporated and the residuewas dissolved in ethyl acetate. The resulting solution was washedsuccessively with 1.0 N HCl, water, and brine, then was dried oversodium sulfate, filtered and concentrated. To obtain the enantiomers insubstantially pure form, Method A (vide infra) was used.

The crude residue was dissolved in TFA (7 mL, 0.09 mol) and the solutionwas stirred for 1 hour. Then excess TFA was evaporated and the residuewas then stirred with ethylenediamine (0.1 mL, 0.001 mol) in methanol (4mL, 0.09 mol) for 16 hours. The mixture was concentrated, and theproduct was purified by preparative-HPLC (C18 eluting with a gradient ofACN/H₂O containing 0.1% TFA) to afford3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanenitriletrifluoroacetate salt (35 mg, 61%). ¹H NMR (300 MHz, d₆-DMSO): δ □12.16(s, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 8.28 (d, 1H), 7.65-7.61 (m, 1H),7.48 (d, 1H), 6.99 (d, 1H), 4.86 (q, 1H), 3.17 (d, 2H), 1.57 (d, 3H);MS(ES):252 (M+1).

Additional analogs were prepared by procedures analogous to thosedescribed in Example 61 using different starting materials foralkylation of the pyrazole ring. For example, the α,β-unsaturatednitriles were prepared by procedures analogous to the following,illustrated for (2E)- and (2Z)-hexenenitrile: To a solution of 1.00 Mpotassium tert-butoxide in THF at 0° C. (24.2 mL) was added a solutionof diethyl cyanomethylphosphonate (4.10 mL, 0.025 mol) in THF (30 mL)dropwise. The bath was removed and the solution was allowed to warm toroom temperature. After reaching room temperature, the solution wasre-cooled to 0° C. and a solution of butanal (2.00 mL, 0.023 mol) in THF(7 mL) was added dropwise. The reaction mixture was allowed to warm toroom temperature and stir overnight. The mixture was diluted with ethylacetate and water. The layers were separated and the aqueous layer wasextracted with three portions of ethyl acetate. The combined organicextracts were washed with brine, dried over sodium sulfate, filtered andconcentrated. This afforded 1.6 g of a crude mixture containing both(2E)- and (2Z)-hexenenitrile, which was used without furtherpurification in the subsequent alkylation step. ¹H NMR (400 MHz, CDCl₃):δ □6.72 (dt, 1H trans olefin), 6.48 (dt, 1H cis olefin), 5.34 (dt, 1Htrans olefin), 5.31-5.30 (m, 1H cis olefin).

Where it was desirable to obtain the enantiomers in substantially pureform, chiral separation was performed by one of the following methods:

A) The separation was performed on the SEM-protected intermediate aftersilica gel chromatography (ethyl acetate/hexanes) by preparative chiralHPLC (OD-H column, eluting with 15% ethanol in hexanes);

B) The separation was performed on the deprotected free base bypreparative chiral HPLC (OD-H column, eluting with 15% ethanol inhexanes);

C) The separation was performed on the SEM-protected intermediate aftersilica gel chromatography (ethyl acetate/hexanes) by preparative chiralHPLC (AD-H column, eluting with 10% ethanol in hexanes);

D) The separation was performed on the SEM-protected intermediate aftersilica gel chromatography (ethyl acetate/hexanes) by preparative chiralHPLC (AD-H column, eluting with 15% ethanol in hexanes);

E) The separation was performed on the SEM-protected intermediate aftersilica gel chromatography (ethyl acetate/hexanes) by preparative chiralHPLC (OD-H column, eluting with 20% ethanol in hexanes; or

F) The separation was performed on the SEM-protected intermediate aftersilica gel chromatography (ethyl acetate/hexanes) by preparative chiralHPLC (OD-H column, eluting with 30% ethanol in hexanes. An OD-H columnrefers to Chiralcel OD-H from Chiral Technologies, Inc 3×25 cm, 5 m. AnAD-H column refers to ChiralPak AD-H from Chiral Technologies, Inc. 2×25cm, 5 μm. The results are summarized for compounds in Table 4 below.

TABLE 4

Method of MS preparation Ex. (ES) and chiral No. Name R (M + 1)separation 62 3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate salt H 238 Ex. 61 63(3S)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]hexanenitriletrifluoroacetate salt and (3R)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]hexanenitrile trifluoroacetate salt Pr 280 Ex. 61Method B 64 (3S)-3-cyclopentyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]- propanenitrile trifluoroacetate saltand (3R)-3-cyclopentyl-3-[4-(1H-pyrrolo]2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-

306 Ex. 61 Method C propanenitrile trifluoroacetate salt 64a(3S)-3-cyclohexyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]- propanenitrile and(3R)-3-cyclohexyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-

320 Ex. 61 Method D propanenitrile

Example 65:(3R)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]hexanenitriletrifluoroacetate salt and(3S)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]hexanenitriletrifluoroacetate salt

Step 1.4-Chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 4-chloropyrrolo[2,3-d]pyrimidine (0.86 g, 0.0056 mol)in DMF (20 mL, 0.2 mol) at 0° C. was added sodium hydride (0.27 g,0.0067 mol) in several portions. The reaction mixture was stirred for anadditional 45 minutes followed by a dropwise addition ofβ-(trimethylsilyl)ethoxy]-methyl chloride (1.2 mL, 0.0067 mol). Theresulting reaction mixture was stirred at 0° C. for 45 min, then wasquenched with water and extracted with ethyl acetate. The organicextract was washed with water, brine, dried over sodium sulfate,filtered and concentrated to give an oil. The crude residue was purifiedby flash column chromatography (0-15% ethyl acetate/hexanes) to yield4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(1.40 g, 88%).

¹H NMR (400 MHz, CDCl₃): δ □8.71 (s, 1H), 7.46 (d, 1H), 6.72 (d, 1H),5.71 (s, 2H), 3.59 (dd, 2H), 0.97 (dd, 2H), 0.00 (s, 9H); MS(ES):284(M+1).

Step 2.4-(1H-Pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(1.4 g, 0.0049 mol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g,0.0074 mol) in DMF (40 mL, 0.5 mol) was added potassium carbonate (2.0g, 0.015 mol) in 15 mL of water. The mixture was purged with a steadystream of nitrogen for 15 minutes.Tetrakis(triphenyl-phosphine)palladium(0) (0.41 g, 0.00036 mol) wasadded and the reaction was heated to 125° C. for 30 min. The mixture wasallowed to cool then diluted with ethyl acetate. The diluted reactionmixture was washed with water, brine, dried over Na₂SO₄ and concentratedto give a solution in a small volume of DMF (about 2-3 mL). Water wasadded, causing the material to form a gum on the walls of the flask.Then water was decanted, and the solids were dissolved in ethyl acetate.The solution was dried over Na₂SO₄, and concentrated in vacuo to afforda yellow solid. The product was triturated with ethyl ether to yield4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidineas a white powder which was dried under vacuum (1 g, 60%). ¹H NMR (300MHz, CDCl₃): δ □10.80 (br s, 1H), 8.93 (s, 1H), 8.46 (s, 2H), 7.46 (d,1H), 6.88 (d, 1H), 5.73 (s, 2H), 3.61 (dd, 2H), 0.98 (dd, 2H), 0.00 (s,9H); MS(ES):316 (M+1).

Step 3

To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(0.050 g, 0.00016 mol) in ACN (1 mL, 0.02 mol) was addedhex-2-enenitrile (0.100 g, 0.00105 mol) (as a mixture of cis and transisomers), followed by DBU(60 μL, 0.0004 mol). The resulting mixture wasstirred at room temperature for 16 hours. The ACN was removed in vacuo.The crude residue was dissolved in ethyl acetate, and was washed with1.0 N HCl, brine, dried over Na₂SO₄ and concentrated. The crude residuewas purified by flash column chromatography (0-70% EtOAc/Hexane) toafford 56 mg of product, which was stirred with 1:1 TFA/DCM for 1 hourand the solvents were evaporated. The resulting product was stirred withmethanol (4 mL, 0.1 mol) containing ethylenediamine (0.1 mL, 0.001 mol)overnight. The solvent was evaporated and the product was purified bypreparative-HPLC (C18 eluting with a gradient of ACN/H₂O containing 0.1%TFA) to afford3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]hexanenitrile asthe trifluroacetate salt. Where desired, the enantiomers were isolatedin substantially pure form by Method A described above for Example 61.¹H NMR (300 MHz, CD₃OD): δ □8.93 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H),7.85 (d, 1H), 7.28 (d, 1H), 4.87-4.77 (m, 1H), 3.26-3.05 (m, 2H),2.20-2.05 (m, 1H), 2.00-1.86 (m, 1H), 1.40-1.10 (m, 2H), 0.95 (t, 3H);MS(ES):281 (M+1).

Example 67: (3R)- and(3S)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

Step 1. (2E)- and (2Z)-3-Cyclopentylacrylonitrile

To a solution of 1.0 M potassium tert-butoxide in THF (235 mL) at 0° C.was added dropwise a solution of diethyl cyanomethylphosphonate (39.9mL, 0.246 mol) in THF (300 mL). The cold bath was removed and thereaction was warmed to room temperature followed by recooling to 0° C.,at which time a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol)in THF (60 mL) was added dropwise. The bath was removed and the reactionwarmed to ambient temperature and stirred for 64 hours. The mixture waspartitioned between diethyl ether and water, the aqueous was extractedwith three portions of ether, followed by two portions of ethyl acetate.The combined extracts were washed with brine, then dried over sodiumsulfate, filtered and concentrated in vacuo to afford a mixturecontaining 24.4 g of olefin isomers which was used without furtherpurification (89%).

¹H NMR (400 MHz, CDCl₃): δ 6.69 (dd, 1H, trans olefin), 6.37 (t, 1H, cisolefin), 5.29 (dd, 1H, trans olefin), 5.20 (d, 1H, cis olefin),3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, trans product),1.98-1.26 (m, 16H).

Step 2. (3R)- and(3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(15.0 g, 0.0476 mol) in ACN (300 mL) was added3-cyclopentylacrylonitrile (15 g, 0.12 mol) (as a mixture of cis andtrans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixturewas stirred at room temperature overnight. The ACN was evaporated. Themixture was diluted with ethyl acetate, and the solution was washed with1.0 N HCl. The organic layer was back-extracted with three portions ofethyl acetate. The combined organic extracts were washed with brine,dried over sodium sulfate, filtered and concentrated. The crude productwas purified by silica gel chromatography (gradient of ethylacetate/hexanes) to yield a viscous clear syrup, which was dissolved inethanol and evaporated several times to remove ethyl acetate, to afford19.4 g of racemic adduct (93%). The enantiomers were separated bypreparative-HPLC, (OD-H, 15% ethanol/hexanes) and used separately in thenext step to generate their corresponding final product. The finalproducts (see Step 3) stemming from each of the separated enantiomerswere found to be active JAK inhibitors; however, the final productstemming from the second peak to elute from the preparative-HPLC wasmore active than its enantiomer.

¹H NMR (300 MHz, CDCl₃): δ 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H),6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H),2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03-1.88 (m, 1H), 1.80-1.15 (m, 7H),0.92 (t, 2H), −0.06 (s, 9H); MS(ES):437 (M+1).

Step 3

To a solution of3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(6.5 g, 0.015 mol, R or S enantiomer as isolated above) in DCM (40 mL)was added TFA (16 mL) and this was stirred for 6 hours. The solvent andTFA were removed in vacuo. The residue was dissolved in DCM andconcentrated using a rotary evaporator two further times to remove asmuch as possible of the TFA. Following this, the residue was stirredwith ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL) overnight. Thesolvent was removed in vacuo, water was added and the product wasextracted into three portions of ethyl acetate. The combined extractswere washed with brine, dried over sodium sulfate, decanted andconcentrated to afford the crude product which was purified by flashcolumn chromatography (eluting with a gradient of methanol/DCM). Theresulting mixture was further purified by preparative-HPLC/MS (C18eluting with a gradient of ACN/H₂O containing 0.15% NH₄OH) to affordproduct (2.68 g, 58%).

¹H NMR (400 MHz, D₆-dmso): δ 12.11 (br s, 1H), 8.80 (s, 1H), 8.67 (s,1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.98 (d, 1H), 4.53 (dt, 1H), 3.27 (dd,1H), 3.19 (dd, 1H), 2.48-2.36 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.13 (m,7H); MS(ES):307 (M+1).

Additional analogs provided in the following Tables were prepared byprocedures analogous to those described in, for example, Examples 61 and65, using different starting materials such as different α,β-unsaturatednitriles in Step 3. Isolation of the enantiomers in substantially pureform was achieved by the indicated chiral separation method describedabove (A-F) preceding Table 4. Where the product was isolated as thefree amine, the product following deprotection was purified bypreparative-HPLC (C18 eluting with a gradient of ACN/H₂O containing0.15% NH₄OH) instead of preparative-HPLC (C18 eluting with a gradient ofACN/H₂O containing 0.1% TFA). This is referred to as “modification G”.The results are summarized in Table 5 according to the followingstructure:

TABLE 5

MS Method of Ex. (ES) preparation and No. Name R′,R″ (M + 1) chiralseparation 66 (3R)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- Me, H 253 Example65, 4-yl)-1H-pyrazol-1-yl]butanenitrile Method A trifluoroacetate saltand (3S)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile trifluoroacetate salt 67(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1- yl]propanenitrile trifluoroacetatesalt and (3S)-3-cyclopentyl-3-[4-(7H-pyrroo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-

307 Example 67 yl]propanenitrile trifluoroacetate salt 682-methyl-3-[4-(7H-pyrrolo[2,3- N, Me 253 Example 65,d]pyrimidin-4-yl)-1H-pyrazol-1- Not separated yl]propanenitriletrifluoroacetate salt 68a (3R)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- Et, H267 Example 65, 4-yl)-1H-pyrazol-1-yl]pentanenitrile modification G, andMethod E (3S)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile 68b(3R)-5-methyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl]hexanenitrile and (3S)-5-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-

295 Example 65, modification G, Method A yl]hexanenitrile 68c(3R)-3-cyclohexyl-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile and (3S)-3-cyclohexyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-

321 Example 65, modification G, Method A pyrazol-1-yl]propanenitrile 68d(3R)-4-cyclopropyl-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile and (3S)-4-cyclopropyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- pyrazol-1-yl]butanenitrile

279 Example 65, modification G, Method F

Example 69:4-{1-[(1S)-1-Methylbutyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate salt and4-{1-[(1R)-1-Methylbutyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate salt

A solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(0.050 g, 0.00016 mol) in DMF (2 mL, 0.02 mol) was cooled in an ice bathand to this was added sodium hydride (0.013 g, 0.00032 mol). Theresulting mixture was stirred for 10 minutes, followed by an addition of2-bromopentane (0.030 mL, 0.00024 mol). The cooling bath was thenremoved and the reaction was stirred at room temperature for 3 hours, atwhich time a further portion of 2-bromopentane (0.015 mL, 0.00012 mol)was added. After 45 minutes, water was added and the reaction mixturewas extracted with three portions of ethyl acetate. The combinedextracts were washed with brine, dried over sodium sulfate, filtered,and concentrated. The residue was stirred with TFA (3 mL, 0.04 mol) andDCM (3 mL, 0.05 mol) for 3.5 hours, then the solvent was removed invacuo. The residue was then stirred with NH₄OH (1.5 mL) in MeOH (4 mL)for 16 hours. The solvent was evaporated and the product was purified bypreparative-HPLC (C18 eluting with a gradient of ACN/H₂O containing 0.1%TFA) to afford4-[1-(1-methylbutyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine as thetrifluoroacetate salt (25 mg, 44%). ¹H NMR (300 MHz, CD₃OD): δ 8.83 (s,1H), 8.75 (s, 1H), 8.43 (s, 1H), 7.77 (d, 1H), 7.24 (d, 1H), 4.63-4.50(m, 1H), 2.07-1.91 (m, 1H), 1.88-1.74 (m, 1H), 1.58 (d, 3H), 1.38-1.09(m, 2H), 0.93 (t, 3H); MS(ES):256 (M+1).

Isolation of the enantiomers in substantially pure form was achieved byseparation of the racemic free base (isolated by flash columnchromatography after deprotection, eluting with a MeOH/DCM gradient)using HPLC (OD-H, eluting with 5% isopropanol/hexanes).

Example 69a:4-Methyl-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile

Step 1. Ethyl3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanoate

A solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(12.1 g, 0.0384 mol), 2-butenoic acid, 3-methyl-, ethyl ester (16.0 mL,0.115 mol) and DBU (14.3 mL, 0.0959 mol) in ACN (100 mL) was heated atreflux for 3.5 hours. The solvent was removed in vacuo. The residue wasdiluted with water, extracted with ethyl acetate, and the combinedorganic extracts were washed with saturated ammonium chloride, driedover sodium sulfate, and concentrated. The crude residue was purified byflash column chromatography (ethyl acetate/hexanes) to yield the desiredproduct (15.5 g, 91%).

¹H NMR (400 MHz, CDCl₃): δ □8.83 (s, 1H), 8.36 (s, 1H), 8.27 (s, 1H),7.37 (d, 1H), 6.80 (d, 1H), 5.66 (s, 2H), 4.03 (q, 2H), 3.54 (dd, 2H),2.98 (s, 2H), 1.80 (s, 6H), 1.13 (t, 3H), 0.91 (dd, 2H), −0.07 (s, 9H);MS(ES):444 (M+1).

Step 2.3-Methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butan-1-ol

To a solution of ethyl3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]butanoate(15.4 g, 0.0347 mol) in THF (151 mL) at −78° C. was added 1.00 Mdiisobutylaluminum hydride in DCM (84.5 mL) dropwise. The reaction wasstirred for 2 hours with slow warming to −10° C. The mixture wasquenched with water, then was treated with potassium sodium tartratetetrahydrate and water. The mixture was stirred for 1 hour, then wasextracted with ethyl acetate. The extracts were washed with water andbrine, then dried with sodium sulfate, filtered, and concentrated invacuo. The crude residue was purified by flash column chromatography toyield the desired product (13.8 g, 99%).

¹H NMR (300 MHz, CDCl₃): δ 8.83 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H),7.38 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 3.65 (dd, 2H), 3.54 (dd, 2H),2.21 (t, 2H), 1.72 (s, 6H), 0.91 (dd, 2H), −0.07 (s, 9H); MS(ES):402(M+1).

Step 3.3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butan-1-ol

A solution of3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butan-1-ol(13.8 g, 0.0344 mol) in TFA (20 mL) was stirred for 1 hour. The mixturewas then concentrated in vacuo and the residue was stirred for 2 hoursin a mixture of methanol (30 mL), ammonium hydroxide (30 mL), andethylenediamine (8 mL). The mixture was then concentrated, and theresidue was diluted with water and extracted with several portions of15% IPA/CH₂Cl₂. The combined extracts were dried over sodium sulfate andconcentrated in vacuo to give 20 g of white solid. The solid wastriturated with ether and the product was isolated by filtration to givethe product as a white solid (7.75 g, 83%).

¹H NMR (400 MHz, CDCl₃): δ □9.99 (s, 1H), 8.83 (s, 1H), 8.39 (s, 1H),8.28 (s, 1H), 7.38 (dd, 1H), 6.80 (dd, 1H), 3.66 (t, 2H), 2.72 (br s,1H), 2.22 (t, 2H), 1.74 (s, 6H); MS(ES):272 (M+1).

Step 4.3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butylmethanesulfonate

A solution of3-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butan-1-ol(6.61 g, 0.0244 mol) in DCM (300 mL) at 0° C. was treated with TEA (3.74mL, 0.0268 mol), followed by methanesulfonyl chloride (2.07 mL, 0.0268mol). The reaction was stirred for 1 hour, and was then concentrated invacuo. The crude residue was purified by flash column chromatography toafford the desired product (4.9 g, 57%).

¹H NMR (400 MHz, d₆-dmso): δ □12.45 (s, 1H), 9.50 (s, 1H), 9.35 (s, 1H),8.83 (s, 1H), 7.79 (dd, 1H), 7.11 (dd, 1H), 4.75 (t, 1H), 3.30 (s, 3H),2.85 (t, 1H), 1.75 (s, 6H); MS(ES):254 (M-CH₃SO₃H+1).

Step 5.4-Methyl-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile

3-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butylmethanesulfonate (2.97 g, 8.50 mmol), DMF (120 mL) and sodium cyanide(6.21 g, 0.127 mol) were distributed evenly into six 20 mL microwavablevessels, each of which was heated in the microwave reactor for 4000seconds at 125° C. The contents of the vials were combined and werediluted with 400 mL water and extracted with five 150 mL portions ofethyl acetate. The combined extracts were dried over sodium sulfate, andthe solvent was removed in vacuo. The crude residue was purified byflash column chromatography to yield the desired product (1.40 g, 59%).

¹H NMR (400 MHz, CDCl₃): δ □9.52 (br s, 1H), 8.83 (s, 1H), 8.34 (s, 1H),8.29 (s, 1H), 7.39 (dd, 1H), 6.81 (dd, 1H), 2.38 (dd, 2H), 2.16 (dd,2H), 1.73 (s, 6H); MS(ES):281 (M+1).

The analogs in Table 5a were prepared according to the above methoddescribed for Example 69a. For Example 69b, a conjugate acceptor wasused and prepared as described in Perkin Trans. 1, 2000, (17),2968-2976, and Steps 4&5 were performed before Step 3.

TABLE 5a MS Ex. (ES) No. Structure Name (M + 1) 69b

3-1-[4-(7H- pyrrolo[2,3-d]- pyrimidin-4-yl)- 1H-pyrazol-1-yl]cyclopropyl- propanenitrile 279 69c

(4S)- and (4R)-4-[4(7H- pyrrolo[2,3-d] pyrimidin-4-yl)- 1H-pyrazol-1-yl]pentanenitrile 267

Example 69d:3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

Step 1. Senecionitrile

To a solution of 1.0 M potassium tert-butoxide in THF (2.0 mL) at 0° C.was added a solution of diethyl cyanomethylphosphonate (0.33 mL, 2.06mmol) in THF (4 mL) dropwise. The cold bath was removed and the reactionwas warmed to room temperature. The reaction was then re-cooled to 0° C.and acetone (0.20 mL, 2.81 mmol) was added dropwise. The cooling bathwas then removed and the reaction was allowed to warm to roomtemperature and stir overnight. The reaction was diluted with water, thelayers separated, and the aqueous extracted with ethyl acetate. Theextracts were washed with brine, dried over sodium sulfate, filtered andconcentrated. The product was used without further purification (339 mg,67%).

¹H NMR (300 MHz, CDCl₃): δ □5.10 (br s, 1H), 2.05 (s, 3H), 1.92 (s, 3H).

Step 2.3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crudesenecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 μL, 0.002 mol)and the resulting mixture was heated to 60° C. for 23 hours. The mixturewas cooled to room temperature and the ACN was evaporated. The mixturewas diluted with ethyl acetate and washed with dilute HCl and brine. Theorganic solution was dried over sodium sulfate, filtered andconcentrated. Purification by silica gel chromatography (ethylacetate/hexanes) afforded the desired product.

¹H NMR (300 MHz, d₆-dmso): δ □8.83 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H),7.39 (d, 1H), 6.80 (d, 1H), 5.66 (s, 2H), 3.54 (dd, 2H), 3.08 (s, 2H),1.84 (s, 6H), 0.91 (dd, 2H), −0.07 (s, 9H); MS(ES):397 (M+1).

To a solution of this product in DCM at 0° C. was added TFA sufficientto comprise 20% of the total volume. The solution was stirred at thistemperature for 30 min, then at ambient temperature for 2 hours and 15minutes. The solvents were removed in vacuo and the residue was stirredwith methanol (10 mL) and ethylenediamine (0.4 mL, 0.006 mol) overnight.The solvent was evaporated and the product was purified bypreparative-HPLC/MS (C18 column eluting with a gradient of ACN/H₂Ocontaining 0.15% NH₄OH) to afford the product (25 mg, 14%).

¹H NMR (300 MHz, d₆-dmso): δ □12.08 (s, 1H), 8.68 (s, 2H), 8.39 (s, 1H),7.59 (d, 1H), 7.05 (d, 1H), 3.32 (s, 2H), 1.73 (s, 6H); MS(ES):267(M+1).

Examples 69e and 69f in Table 5b were prepared by a method analogous tothat described above for Example 69d, with unsaturated nitriles preparedeither according to published literature procedures, or by the method inStep 1.

TABLE 5b MS Ex. (ES) No. Structure Name (M + 1) 69e

3-ethyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile 295 69f

1-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclopropylacetonitrile 265

Additional analogs were prepared by procedures analogous to thosedescribed in Example 69, using different starting materials such asalternative bromide or mesylate compounds for the nucleophilicsubstitution step. Where the free amine was obtained as the product, theproduct was purified after deprotection either by silica gelchromatography (eluting with 5% methanol in DCM) or by preparative-HPLC(C18 eluting with a gradient of ACN/H₂O containing 0.15% NH₄OH). Theresults are summarized for compounds listed in Table 6.

TABLE 6

MS Ex. (ES) No. Name —(Y)_(n)—Z (M + 1) 70 4-1-[(2R)-pyrrolidin-2-ylmethyl]-1H- pyrazol-4-yl-7H-pyrrolo[2,3-d]- pyrimidine

269 71 4-(1-[(2R)-1- (methylsulfonyl)pyrrolidin-2-yl]methyl-1H-pyrazol-4-72yl)-7H- pyrrolo[2,3-d]pyrimidine

347 73 ethyl 2-methyl-2- [4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanoate trifluoroacetate salt

300

Example 74:(2Z)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-acrylonitrile

Step 1. 3-Cyclopentylprop-2-ynenitrile

To a solution of cyclopentylacetylene (0.50 g, 5.3 mmol) in THF (5 mL)at −78° C. was added 2.5 M n-butyllithium in hexane (2.23 mL). Themixture was stirred for 15 min followed by the dropwise addition ofphenyl cyanate (0.70 g, 5.8 mmol) in THF (3 mL). The reaction was warmedto room temperature. Into the reaction mixture was poured 6 N NaOH, andthe mixture was stirred for 5 minutes. The product was extracted withdiethyl ether. The extracts were washed with 6 N NaOH and with brine,then dried over sodium sulfate, decanted and the solvent was removed invacuo to afford product (600 mg, 95%). ¹H NMR (300 MHz, CDCl₃): δ□2.81-2.68 (m, 1H), 2.07-1.54 (m, 8H).

Step 2.(2Z)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]acrylonitrile

To a mixture of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(0.40 g, 1.2 mmol) and 3-cyclopentylprop-2-ynenitrile (0.30 g, 2.5 mmol)in DMF (8 mL) was added potassium carbonate (0.09 g, 0.6 mmol). Themixture was stirred for 35 min. The reaction was diluted with ethylacetate and brine, and the aqueous portion extracted with three volumesof ethyl acetate. The combined organic extracts were washed with brineagain, then were dried over sodium sulfate, decanted and concentrated invacuo. The crude residue was purified by flash column chromatography(ethyl acetate/hexanes) to yield the desired product (290 mg, 53%).

¹H NMR (400 MHz, CDCl₃): δ □8.98 (s, 1H), 8.87 (s, 1H), 8.46 (s, 1H),7.42 (d, 1H), 6.84 (d, 1H), 5.67 (s, 2H), 5.21 (s, 1H), 3.64-3.55 (m,1H), 3.53 (t, 2H), 2.13-2.01 (m, 2H), 1.83-1.66 (m, 4H), 1.57-1.46 (m,2H), 0.91 (t, 2H), −0.07 (s, 9H); MS(ES):435 (M+1).

Step 3.(2Z)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]acrylonitrile

A solution of(2Z)-3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]acrylonitrile(0.030 g, 0.069 mol) in DCM (3 mL) and TFA (2 mL) was stirred for 1hour. The solvents were removed in vacuo and the product was stirredwith THF (1.5 mL), sodium hydroxide, 50% aqueous solution (0.75 mL) andwater (0.75 mL) for 2 hours. The reaction mixture was neutralized by thedropwise addition of conc. HCl. The product was extracted with ethylacetate. The combined organics were dried over sodium sulfate, filteredand concentrated in vacuo. The crude residue was purified bypreparative-HPLC/MS (C18 column eluting with a gradient of ACN/H₂Ocontaining 0.15% NH₄OH) to afford the desired product (16 mg, 76%).

¹H NMR (400 MHz, d₆-dmso): δ □9.08 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H),7.66 (d, 1H), 7.05 (d, 1H), 5.82 (d, 1H), 3.62-3.54 (m, 1H), 2.00-1.90(m, 2H), 1.76-1.48 (m, 6H); MS(ES):305 (M+1).

Example 75:3-Cyclopentylidene-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile

Step 1.3-Cyclopentylidene-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

To a suspension of 3-cyclopentylprop-2-ynenitrile (0.4 g, 0.003 mol) inACN (10 mL) was added4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(0.53 g, 1.7 mmol) and DBU (0.33 mL, 2.2 mmol). This mixture was stirredat room temperature for 50 minutes. The reaction mixture was partitionedbetween ethyl acetate and dilute HCl. The aqueous portion was separatedand extracted with ethyl acetate. The combined organic extracts werewashed with dilute HCl and brine, were dried over sodium sulfate,filtered and concentrated in vacuo. The crude residue was purified byflash column chromatography (ethyl acetate/hexanes) to yield the desiredproduct (540 mg, 74%).

¹H NMR (300 MHz, CDCl₃): δ 8.85 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H),7.40 (d, 1H), 6.78 (d, 1H), 5.67 (s, 2H), 3.70 (s, 2H), 3.54 (dd, 2H),2.55 (t, 2H), 2.45 (t, 2 h), 1.85 (dddd, 2H), 1.73 (dddd, 2H), 0.91 (dd,2H), −0.06 (s, 9H); MS(ES):435 (M+1).

Step 2.3-Cyclopentylidene-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

A solution of3-cyclopentylidene-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(0.030 g, 0.069 mmol) in DCM (3 mL) and TFA (2 mL) was stirred for 1hour. The solvents were evaporated in vacuo and the product was stirredwith sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75mL) and THF (1.5 mL) for 2 hours. The reaction mixture was neutralizedby dropwise addition of concentrated HCl. The product was extracted withethyl acetate. The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo. The crude residue waspurified by preparative-HPLC/MS (C18 column eluting with a gradient ofACN/H₂O containing 0.15% NH₄OH) to afford the desired product (7 mg,33%).

¹H NMR (400 MHz, d₆-dmso): δ □12.23-12.01 (br s, 1H), 8.78 (s, 1H), 8.69(s, 1H), 8.46 (s, 1H), 7.60 (d, 1H), 7.04 (d, 1H), 3.95 (s, 2H), 2.53(t, 2H), 2.42 (t, 2H), 1.76 (dddd, 2H), 1.65 (dddd, 2H); MS(ES):305(M+1).

Example 76:3-Methyl[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]aminopropanenitriletrifluoroacetate salt

Step 1.4-(1,3-Thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

4-Chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(3.00 g, 0.0106 mol), and 1,3-thiazole (7.50 mL, 0.106 mol) weredissolved in N,N-dimethylacetamide (40.0 mL). The solution wasdistributed in equal portions into four 20 mL microwavable vessels. Intoeach reaction vessel was then added potassium acetate (0.777 g, 7.93mmol) followed by tetrakis(triphenyl-phosphine)palladium(0) (0.60 g, 2.1mmol). Each reaction vessel was heated at 200° C. in the microwavereactor for 30 minutes. The reactions were combined and most of thesolvent was removed in vacuo. The residue was diluted with DCM, filteredand concentrated. Purification by flash column chromatography (ethylacetate/hexanes) afforded the desired product (2.25 g, 64%).

¹H NMR (300 MHz, CDCl₃): δ 8.99 (s, 1H), 8.90 (s, 1H), 8.72 (s, 1H),7.49 (d, 1H), 6.91 (d, 1H), 5.70 (s, 2H), 3.56 (dd, 2H), 0.93 (dd, 2H),−0.05 (s, 9H); MS(ES):333 (M+1).

Step 2.4-(2-Bromo-1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

2.5 M n-Butyllithium in hexane (0.860 mL) was added dropwise to a −78°C. solution of4-(1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(550 mg, 0.0016 mol) in THF (20 mL). The mixture was stirred for 30minutes at −78° C., followed by the slow addition of carbon tetrabromide(658 mg, 0.00198 mol) as a solution in THF (10 mL). After 30 minutes,the mixture was quenched with a small amount of saturated ammoniumchloride, diluted with ether, and dried over sodium sulfate. The residueobtained after filtration and concentration was purified by flash columnchromatography (ethyl acetate/hexanes) to afford the desired product(387 mg, 57%).

¹H NMR (300 MHz, CDCl₃): δ 8.85 (s, 1H), 8.33 (s, 1H), 7.49 (d, 1H),6.83 (d, 1H), 5.69 (s, 2H), 3.55 (dd, 2H), 0.92 (dd, 2H), −0.05 (s, 9H);MS(ES):411, 413 (M+1).

Step 3. 4-(2-Bromo-1,3-thiazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine

A solution of4-(2-bromo-1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidine(370 mg, 0.90 mmol) in DCM (5.0 mL) and TFA (1.0 mL) was stirred at roomtemperature for 7 hours. The mixture was then concentrated, re-dissolvedin methanol (2 mL), and ethylenediamine (0.5 mL) was added. The mixturewas stirred for 6 hours at room temperature. The mixture was dilutedwith DCM (10 mL), and the precipitate was isolated by filtration andwashed with a small amount of DCM to afford desired product (182 mg,72%).

¹H NMR (300 MHz, d₆-dmso): δ □8.74 (s, 1H), 8.70 (s, 1H), 7.76 (d, 1H),7.15 (d, 1H); MS(ES):281,283 (M+1).

Step 4.3-Methyl[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]aminopropanenitrile

A solution of 4-(2-bromo-1,3-thiazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine(31 mg, 0.11 mmol) and 3-(methylamino)propionitrile (103 μL, 0.00110mol) in DMF (1.0 mL, 0.013 mol) was stirred at 90° C. for 2 hours. Thecrude reaction mixture was purified by preparative-HPLC/MS (C18 columneluting with a gradient of ACN/H₂O containing 0.15% NH₄OH) and again bypreparative-HPLC/MS (C18 column eluting with a gradient of ACN/H₂Ocontaining 0.1% TFA) to yield the desired product as thetrifluoroacetate salt (30 mg, 68%).

¹H NMR (300 MHz, d₆-DMSO): δ □12.25 (s, 1H), 8.60 (s, 1H), 8.31 (s, 1H),7.60 (dd, 1H), 7.00 (dd, 1H), 3.89 (t, 2H), 3.20 (s, 3H), 2.94 (t, 2H);MS(ES):285 (M+1).

Example 77: (3S)- and(3R)-3-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]hexanenitrile

Step 1. N-Methoxy-N-methylbutanamide

To a mixture of butanoic acid (1.01 g, 0.0115 mol) andN,O-dimethylhydroxylamine hydrochloride (1.12 g, 0.0115 mol) in DCM (50mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate (5.6 g, 0.013 mol) and TEA (3.2 mL, 0.023 mol). Themixture was stirred overnight at room temperature. The solution was thenwashed with water and brine, dried over sodium sulfate, and concentratedin vacuo. The crude product was purified by flash column chromatography(ether/hexanes). The solvent was removed (235 mbar/40° C.) to afford theproduct (1.33 g, 88%). ¹H NMR (300 MHz, CDCl₃): δ □3.68 (s, 3H), 3.18(s, 3H), 2.40 (t, 2H), 1.74-1.59 (m, 2H), 0.96 (t, 3H).

Step 2.1-[5-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]-butan-1-one

2.5 M n-Butyllithium in hexane (878 μL) was added slowly dropwise to a−78° C. solution of4-(1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(501 mg, 1.37 mmol) in THF (20 mL). After 45 minutes,N-methoxy-N-methylbutanamide (0.360 g, 2.74 mmol) was added. Thereaction was continued at −78° C. for 30 min, and was then allowed toreach room temperature. The reaction was quenched with saturatedammonium chloride, and was extracted with ethyl acetate. The extractswere washed with water and brine, dried over sodium sulfate andconcentrated in vacuo. Flash column chromatography (ethylacetate/hexanes) afforded the product (235 mg, 42%).

¹H NMR (300 MHz, CDCl₃): δ □8.93 (s, 1H), 8.76 (s, 1H), 7.52 (d, 1H),6.92 (d, 1H), 5.71 (s, 2H), 3.56 (dd, 2H), 3.19 (t, 2H), 1.92-1.77 (m,2H), 1.05 (t, 3H), 0.93 (dd, 2H), −0.05 (s, 9H); MS(ES):403 (M+1).

Step 3. (2E)- and(2Z)-3-[5-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]hex-2-enenitrile

To a solution of 1.0 M potassium tert-butoxide in THF (0.605 mL) in THF(4.0 mL) at 0° C. was added diethyl cyanomethylphosphonate (0.102 mL,0.634 mmol) dropwise. The cooling bath was removed and the reaction waswarmed to room temperature. After 30 minutes, a solution of1-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]butan-1-one(232 mg, 0.576 mmol) in THF (3.0 mL) was added dropwise. The reactionwas stirred for 2 hours, and the crude mixture was then adsorbed ontosilica gel and purified by flash column chromatography (ethylacetate/hexanes) to afford the product as a mixture of olefin isomers(225 mg, 92%).

¹H NMR (300 MHz, CDCl₃), major isomer: δ□ 8.89 (s, 1H), 8.65 (s, 1H),7.52 (d, 1H), 6.89 (d, 1H), 6.35 (s, 1H), 5.70 (s, 2H), 3.56 (dd, 2H),2.96 (t, 2H), 1.88-1.72 (m, 2H), 1.08 (t, 3H), 0.93 (dd, 2H), −0.07 (s,9H); MS(ES):426 (M+1).

Step 4. (3S)- and(3R)-3-[5-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]hexanenitrile

Cupric acetate, monohydrate (0.7 mg, 0.004 mmol) and(oxydi-2,1-phenylene)bis(diphenylphosphine) (2 mg, 0.004 mol) was mixedin toluene (0.24 mL). PMHS (30 μL) was added. The mixture was stirredfor 25 minutes at room temperature followed by the addition of(2E)-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]hex-2-enenitrile(51 mg, 0.12 mol) in toluene (0.24 mL) and finally, tert-butyl alcohol(0.043 mL). The resulting mixture was stirred overnight. The crudemixture was purified directly by flash column chromatography (ethylacetate/hexanes) to afford the desired product (39 mg, 76%).

¹H NMR (300 MHz, CDCl₃): δ □8.87 (s, 1H), 8.52 (s, 1H), 7.48 (d, 1H),6.87 (d, 1H), 5.69 (s, 2H), 3.60-3.46 (m, 3H), 2.99-2.82 (m, 2H),2.05-1.89 (m, 2H), 1.50-1.34 (m, 2H), 0.97 (t, 3H), 0.92 (t, 2H), −0.06(s, 9H); MS(ES):428 (M+1).

Step 5. (3S)- and(3R)-3-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]hexanenitrile

TFA (1.0 mL) was added to a solution of3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]hexanenitrile(36 mg, 0.084 mmol) in DCM (4.0 mL) and the mixture was stirred at roomtemperature for 3 hours. The mixture was concentrated, and re-dissolvedin methanol (3 mL), to which ethylenediamine (0.1 mL) was added. After 2hours reaction time, the mixture was concentrated and directly purifiedby preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H₂Ocontaining 0.15% NH₄OH) to afford the desired product (10 mg, 40%). ¹HNMR (300 MHz, CDCl₃): δ □9.96 (br s, 1H), 8.87 (s, 1H), 8.54 (s, 1H),7.51-7.45 (m, 1H), 6.90-6.86 (m, 1H), 3.59-3.44 (m, 1H), 3.01-2.82 (m,2H), 2.06-1.87 (m, 2H), 1.51-1.34 (m, 2H), 0.98 (t, 3H); MS(ES):298(M+1).

Example 78: (3R)- and(3S)-3-Cyclopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]propanenitrile

To a solution of (2E)- and(2Z)-3-cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]acrylonitrile(199 mg, 0.440 mmol) (prepared, for example, as in Example 77, steps 1through 3) in a mixture of ethanol (10 mL) and ethyl acetate (10 mL) wasadded a catalytic amount of 10% palladium on carbon. The mixture wasstirred at room temperature under one atmosphere of hydrogen overnight.It was then subjected to 50 PSI H₂ until the reaction was complete.Filtration and removal of solvent afforded an oil which was dissolved inDCM (4 mL) and TFA (1 mL). The solution was stirred until startingmaterial was consumed and the mixture was then concentrated andre-dissolved in methanol (3 mL), to which ethylenediamine (0.4 mL) wasadded. The solution was stirred at room temperature for one hour, andwas concentrated in vacuo. The crude mixture was purified bypreparative-HPLC/MS (C18 column eluting with a gradient of ACN/H₂Ocontaining 0.15% NH₄OH) to afford the desired product (36 mg, 25%).

¹H NMR (400 MHz, CDCl₃): δ □10.44 (br s, 1H), 8.89 (s, 1H), 8.56 (s,1H), 7.50 (dd, 1H), 6.89 (dd, 1H), 3.34 (dt, 1H), 2.98 (dd, 1H), 2.89(dd, 1H), 2.44-2.31 (m, 1H), 2.07-1.96 (m, 1H), 1.80-1.52 (m, 5H),1.40-1.24 (m, 2H); MS(ES):324 (M+1).

The following compounds of Table 5c were prepared (as racemic mixtures)as described by Example 77, 78 or 86, as indicated in the followingtable, by using different Weinreb amides (as prepared in Example 77,Step 1):

TABLE 5c

Ex. MS (ES) Method of No. Name R (M + 1) preparation 795-methyl-3-[5-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1,3-thiazol-2-yl]-hexanenitrile

312 Ex. 77 80 3-pyridin-3-yl-3-[5-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1,3-thiazol-2-yl]- propanenitrile

333 Ex. 78 81 3-(5-bromopyridin-3-yl)-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol- 2-yl]propanenitrile

411, 413 Ex. 77 82 5-2-cyano-1-[5-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1,3-thiazol-2-yl]- ethylnicotinonitrile

358 Ex. 77 through Step 4, then Ex. 431 excluding purification then Ex.77, Step 5 83 3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Me 270 Ex. 86,Step 3 1,3-thiazol-2-yl]butanenitrile subjected to conditions of Ex. 77,Steps 4 & 5 83A 3-pyridin-4-yl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2- yl]propanenitrile

333 Ex. 78 83B 4-2-cyano-1-[5-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1,3-thiazol-2-yl]- ethylpyridine-2-carbonitriletrifluoroacetate salt

358 Ex. 77 through Step 3, then Ex. 431 excluding purification then Ex.78, purified by prep- HPLC/MS using H₂O/ACN containing 0.1% TFA 83C3-pyridin-2-yl-3-[5-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1,3-thiazol-2-yl]- propanenitrile

333 Ex. 78

Example 84: (2S)- and(2R)-2-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]pentanenitrile

Step 1. (2S)- and(2R)-2-[5-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]pentanenitrile

To a mixture of1-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]butan-1-one(prepared as in Example 77) (101 mg, 0.251 mmol) andp-tolylsulfonyl-methyl isocyanide (147 mg, 0.753 mmol) in a mixture ofDMSO (5.0 mL) and ethanol (61 μL) was added 1.0 M potassiumtert-butoxide in THF (753 μL). The mixture was then heated to 45° C. for2 hours. Upon cooling to room temperature, the mixture was quenched bythe addition of saturated ammonium chloride, followed by water. Theproduct was extracted with ether, and the extracts were washed withwater and brine, dried over sodium sulfate, filtered and concentrated invacuo. Flash column chromatography (ethyl acetate/hexanes) afforded theproduct (39 mg, 25%).

¹H NMR (400 MHz, CDCl₃): δ 8.88 (s, 1H), 8.52 (s, 1H), 7.50 (d, 1H),6.87 (d, 1H), 5.70 (s, 2H), 4.32 (dd, 1H), 3.55 (dd, 2H), 2.20-2.11 (m,2H), 1.71-1.57 (m, 2H), 1.03 (t, 3H), 0.93 (dd, 2H); MS(ES):414 (M+1).

Step 2. (2S)- and(2R)-2-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]pentanenitrile

A solution of2-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]pentanenitrile(59 mg, 0.093 mmol) in DCM (3 mL) and TFA (0.5 mL) was stirred at roomtemperature for 4 hours. The mixture was then concentrated, and theresidue was then dissolved in methanol (3 mL) to which ethylenediamine(0.3 mL) was then added. The solution was stirred at room temperaturefor 40 minutes. The solvent was removed in vacuo, and the crude mixturewas purified by preparative-HPLC/MS (C18 column eluting with a gradientof ACN/H₂O containing 0.15% NH₄OH) to afford the desired product (20 mg,76%).

¹H NMR (400 MHz, CDCl₃): δ □9.66 (br s, 1H), 8.88 (s, 1H), 8.54 (s, 1H),7.49 (dd, 1H), 6.88 (dd, 1H), 4.33 (dd, 1H), 2.23-2.12 (m, 2H),1.75-1.60 (m, 2H), 1.04 (t, 3H); MS(ES):284 (M+1).

Example 85: (4S)- and(4R)-4-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]heptane-nitrile

To a solution of triethyl phosphonoacetate (188 mg, 0.838 mmol) in THF(6.0 mL) at 0° C. was added 1.0 M potassium tert-butoxide in THF (840μL). The mixture was then allowed to warm to room temperature followedby re-cooling to 0° C., at which time1-[5-(7-[2-(trimethylsilyl)ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]butan-1-one(prepared as in Example 77) (225 mg, 0.559 mmol) in THF (4.0 mL) wasadded. The mixture was stirred at room temperature for 1.5 hours, atwhich time it was quenched with water and extracted with ethyl acetate.The combined extracts were washed with water and brine, dried oversodium sulfate and concentrated in vacuo. Flash column chromatographyafforded the product as a mixture of olefin isomers (222 mg, 84%).

MS(ES):473 (M+1).

Ethyl3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]hex-2-enoateas a mixture of (2E)- and (2Z)-isomers (222 mg, 0.470 mmol) wasdissolved in ethanol (10 mL), and a catalytic amount of 10% Pd—C wasadded. The mixture was stirred under an atmosphere of hydrogen, providedby a balloon, for 16 hours. Filtration and concentration in vacuoafforded the desired product (201 mg, 90%). MS(ES):475 (M+1).

To a solution of ethyl3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]hexanoate(201 mg, 0.423 mmol) in THF (5.0 mL) at −78° C. was added 1.00 Mdiisobutylaluminum hydride in DCM (1.06 mL). The mixture was allowed towarm to −10° C. slowly over 1.5 hours, followed by the addition ofpotassium sodium tartrate tetrahydrate, water, and ether. The mixturewas stirred for 1 hour, then layers were separated, and the aqueouslayer was extracted further with ethyl acetate. The organic extractswere washed with water and brine, dried over sodium sulfate andconcentrated in vacuo to afford desired product (176 mg, 96%).MS(ES):433 (M+1).

A solution of3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]hexan-1-ol(88 mg, 0.20 mmol) in TFA (2 mL) was stirred for 30 minutes. The TFA wasthen evaporated and the residue was stirred in methanol (2 mL)containing ethylenediamine (0.2 mL) and a drop of water for 30 minutes.Purification via preparative-HPLC/MS (C18 eluting with a gradient ofACN/H₂O containing 0.15% NH₄OH) afforded the desired product (36 mg,58%).

MS(ES):303 (M+1).

To a mixture of3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]hexan-1-ol (36mg, 0.12 mmol) and TEA (19.9 μL, 0.143 mmol) in DCM (5 mL) at 0° C. wasadded methanesulfonyl chloride (11.0 μL, 0.143 mmol). After stirring for10 minutes, the solution was concentrated and dissolved in DMSO (1.6 mL)and sodium cyanide (23 mg, 0.48 mmol) was added. The mixture was thenheated at 125° C. in the microwave for 30 minutes. The mixture was thenpurified directly using preparative-HPLC/MS (C18 eluting with a gradientof ACN/H₂O containing 0.15% NH₄OH) to afford the desired product (10 mg,27%).

¹H NMR (400 MHz, CDCl₃): δ □9.37 (br s, 1H), 8.86 (s, 1H), 8.52 (s, 1H),7.46 (dd, 1H), 6.88 (dd, 1H), 3.34-3.25 (m, 1H), 2.47-2.30 (m, 2H),2.22-2.12 (m, 2H), 1.95-1.71 (m, 2H), 1.44-1.31 (m, 2H), 0.94 (t, 3H);MS(ES):312 (M+1).

Example 86:3-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]pentanedinitrile

Step 1. N-Methoxy-2-[(4-methoxybenzyl)oxy]-N-methylacetamide

To a mixture of [(4-methoxybenzyl)oxy]acetic acid (Bioorganic andMedicinal Chemistry Letters, 2001, pp. 2837-2841) (6.86 g, 0.0350 mol)and N,O-dimethylhydroxylamine hydrochloride (3.41 g, 0.0350 mol) in DCM(100 mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate (17 g, 0.038 mol) followed by TEA (9.7 mL, 0.070mol). The resulting mixture was stirred overnight at room temperature.The solution was then washed with water, 0.5 M HCl, saturated NaHCO₃,and brine, then was dried over sodium sulfate, filtered and concentratedin vacuo. Flash column chromatography (ether/hexanes) afforded thedesired product (5.75 g, 69%).

Step 2.2-[(4-Methoxybenzyl)oxy]-1-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1,3-thiazol-2-yl]ethanone

To a solution of4-(1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(2.12 g, 6.38 mmol) in THF (70 mL) at −78° C. was added 2.5 Mn-butyllithium in hexane (3.06 mL) slowly dropwise. After stirring for30 minutes, N-methoxy-2-[(4-methoxybenzyl)oxy]-N-methylacetamide (2.29g, 9.56 mmol) was added. The reaction was continued for 30 minutesfollowing the addition, at −78° C., then the cooling bath was removedand the reaction was quenched with saturated ammonium chloride andextracted with ether. The extracts were dried with sodium sulfate andconcentrated in vacuo. The crude mixture was purified by flash columnchromatography (ethyl acetate/hexanes) to afford desired product (2.16g, 66%).

¹H NMR (300 MHz, CDCl₃): δ □8.93 (s, 1H), 8.72 (s, 1H), 7.53 (d, 1H),7.37 (d, 2H), 6.91 (d, 2H), 6.89 (d, 1H), 5.70 (s, 2H), 5.00 (s, 2H),4.70 (s, 2H), 3.81 (s, 3H), 3.56 (dd, 2 h), 0.93 (dd, 2H), −0.05 (s,9H); MS(ES):511 (M+1).

Step 3. (2E)- and(2Z)-4-[(4-Methoxybenzyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]but-2-enenitrile

To a solution of 1 M potassium tert-butoxide in THF (4.44 mL) in THF (30mL) at 0° C. was added diethyl cyanomethylphosphonate (820 mg, 0.0046mol) dropwise. The bath was removed and the reaction was warmed to roomtemperature. After 30 minutes, a solution of2-[(4-methoxybenzyl)-oxy]-1-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]-ethanone(2.16 g, 0.00423 mol) in THF (20 mL) was added dropwise. The reactionwas stirred for 1 hour, and was then quenched with a small amount ofsaturated ammonium chloride, diluted with ether, dried over sodiumsulfate and concentrated in vacuo. Purification by flash columnchromatography, eluting with a gradient of 0-35% ethyl acetate/hexanesafforded the desired product as a mixture of olefin isomers in nearlyequal amounts (1.76 g, 78%).

¹H NMR (400 MHz, CDCl₃): δ 8.90 (s, 1H), 8.88 (s, 1H), 8.71 (s, 1H),8.67 (s, 1H), 7.50 (d, 2H), 7.35 (dd, 2H), 7.31 (dd, 2H), 6.92 (dd, 2H),6.90 (dd, 2H), 6.86 (d, 2H), 6.62 (s, 1H), 6.10 (t, 1H), 5.70 (s, 4H),4.75 (s, 2H), 4.72 (d, 2H), 4.64 (s, 4H), 3.82 (s, 3H), 3.81 (s, 3H),3.56 (dd, 2H), 3.55 (dd, 2H), 0.96-0.90 (m, 4H), −0.05 (s, 9H), −0.054(s, 9H); MS(ES):534 (M+1).

Step 4.4-[(4-Methoxybenzyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1,3-thiazol-2-yl]butanenitrile

(2E)- and(2Z)-4-[(4-Methoxybenzyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]but-2-enenitrile(880 mg, 1.6 mmol) was dissolved in a mixture of ethanol (20 mL) andethyl acetate (20 mL). A catalytic amount of 10% Pd—C was added. Themixture was shaken under 50 PSI of hydrogen. The mixture was filteredand concentrated in vacuo to afford the desired product (0.85 g, 99%).MS(ES):536 (M+1).

Step 5.3-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]pentanedinitrile

4-[(4-Methoxybenzyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1,3-thiazol-2-yl]butanenitrile(251 mg, 0.468 mmol) in DCM (10 mL) was treated withdichlorodicyanoquinone (DDQ) (434 mg, 1.87 mmol), followed by water (376μL). After 1.5 hours, saturated sodium bicarbonate and water were added,and the reaction was extracted with ethyl acetate three times. Theextracts were washed with water, brine, dried over sodium sulfate,filtered and concentrated in vacuo to afford the crude product which wasused without further purification.

A solution of the above prepared4-hydroxy-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]butanenitrilein DCM (12 mL) at 0° C. was treated sequentially with TEA (130 μL, 0.94mmol) and methanesulfonyl chloride (73 μL, 0.94 mmol). After 1 hourreaction time, the mixture was diluted with water and extracted withethyl acetate three times. The extracts were washed with water andbrine, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was then dissolved in DMSO (5 mL) and sodium cyanide (110mg, 2.3 mmol) was added. After 30 minutes, the mixture was diluted withwater, extracted with ether, washed with water, brine and dried oversodium sulfate. Concentration and purification by flash columnchromatography (ethyl acetate/hexanes) afforded the desired product (14mg, 7%). MS(ES):425 (M+1).

A solution of3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]pentanedinitrile(14 mg, 0.033 mmol) in DCM (3 mL) containing TFA (0.6 mL) was stirredfor 4 hours. The mixture was then concentrated and the residue wasredissolved in methanol (2 mL) to which ethylenediamine (0.4 mL) wasthen added. After 1 hour reaction time, the product was purified bypreparative-HPLC/MS (C18 eluting with a gradient of ACN/H₂O containing0.15% NH₄OH) to afford the desired product (6 mg, 62%).

¹H NMR (400 MHz, d₆-dmso): δ □12.27 (br s, 1H), 8.84 (s, 1H), 8.76 (s,1H), 7.75 (d, 1H), 7.14 (d, 1H), 4.14 (m, 1H), 3.17 (d, 4H); MS(ES):295(M+1).

Example 87:(3R)-3-Cyclopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-oxazol-2-yl]-propanenitrileand(3S)-3-Cyclopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-oxazol-2-yl]propanenitrile

Step 1.4-(1,3-Oxazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

A mixture of4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(0.440 g, 1.55 mmol), 1,3-oxazole (0.306 mL, 4.65 mmol), potassiumacetate (0.456 g, 4.65 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.179 g, 0.155 mmol) inN,N-dimethylacetamide (8.0 mL) was heated to 200° C. in the microwavereactor for 30 minutes. Most of the solvent was removed in vacuo. Theresulting residue was diluted with DCM, and was filtered andconcentrated. Flash column chromatography (ethyl acetate/hexanes)afforded the product (330 mg, 67%).

¹H NMR (400 MHz, CDCl₃): δ 8.96 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H),7.54 (d, 1H), 7.08 (d, 1H), 5.76 (s, 2H), 3.60 (t, 2H), 0.98 (t, 2H),0.00 (s, 9H); MS(ES):317 (M+1).

Step 2.Cyclopentyl[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-oxazol-2-yl]methanone

n-Butyllithium in hexane (1.6 M, 0.30 mL) was added slowly dropwise to a−78° C. solution of4-(1,3-oxazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(140.0 mg, 0.44 mmol) in THF (10.0 mL). After 20 minutes, 1.0 M zincdichloride in ether (0.53 mL) was added. The reaction mixture was thenstirred for 60 min at 0° C. Following this, copper(I) iodide (84 mg,0.44 mmol) was added, and this mixture was allowed to stir for 10minutes. Cyclopentanecarbonyl chloride (108 μL, 0.885 mmol) was thenadded. The reaction was stirred at 0° C. for a further 1 hour, at whichtime it was allowed to warm to room temperature. The reaction wasquenched by the addition of saturated NH₄Cl solution, and was extractedwith ethyl acetate. The extracts were washed with water and brine, driedover sodium sulfate, filtered and concentrated in vacuo. Flash columnchromatography (ethyl acetate/hexanes) afforded the product (97 mg,53%).

¹H NMR (400 MHz, CDCl₃): δ 8.96 (s, 1H), 8.21 (s, 1H), 7.56 (d, 1H),7.22 (d, 1H), 5.76 (s, 2H), 3.60 (t, 2H), 3.56 (t, 1H), 2.23-1.56 (m,8H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):413 (M+1).

Step 3. (3R)- and(3S)-3-Cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-oxazol-2-yl]propanenitrile

To a solution of 1.0 M potassium tert-butoxide in THF (0.355 mL) and THF(3 mL) at 0° C. was added diethyl cyanomethylphosphonate (66 mg, 0.37mmol) dropwise. The cold bath was removed and the reaction was warmed toroom temperature. After 30 minutes, a solution ofcyclopentyl[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-oxazol-2-yl]methanone(1.40E2 mg, 0.338 mmol) in THF (2.0 mL) was added dropwise. After 3hours reaction time, the mixture was adsorbed onto silica gel, and flashcolumn chromatography (ethyl acetate/hexanes) afforded the desiredproduct as a mixture of olefin isomers (89 mg, 60%).

MS(ES):436 (M+1).

To a mixture of cupric acetate, monohydrate (4.0 mg, 0.020 mmol) and(oxydi-2,1-phenylene)bis(diphenylphosphine) (11 mg, 0.020 mmol) intoluene (0.40 mL, 0.0038 mol) was added PMHS (50 μL). The resultingmixture was stirred for 25 minutes at room temperature, followed by theaddition of (2E)- and(2Z)-3-cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1,3-oxazol-2-yl]acrylonitrile(88 mg, 0.20 mmol) in toluene (0.40 mL), and then tert-butyl alcohol(0.072 mL). After failure to react at room temperature over 16 hours,additional cupric acetate, monohydrate and(oxydi-2,1-phenylene)bis(diphenylphosphine) (0.10 mol equivalent each)were added and the reaction mixture was heated at 60° C. for 16 hours.The crude mixture was subjected to flash column chromatography (ethylacetate/hexanes) to afford the desired product (21 mg, 23%).

¹H NMR (400 MHz, CDCl₃): δ 8.96 (s, 1H), 8.02 (s, 1H), 7.56 (d, 1H),7.10 (d, 1H), 5.76 (s, 2H), 3.60 (t, 2H), 3.38-3.30 (m, 1H), 3.03 (dd,1H), 2.95 (dd, 1H), 2.60-2.40 (m, 1H), 2.10-2.00 (m, 1H), 1.85-1.15 (m,7H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):438 (M+1).

Step 4. (3R)- and(3S)-3-Cyclopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-oxazol-2-yl]-propanenitrile

A solution of3-cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1,3-oxazol-2-yl]propanenitrile(20.0 mg, 0.0457 mmol) was stirred with TFA (0.1 mL) in DCM (0.2 mL) for6 hours. The solvent was removed, and the resulting residue was stirredovernight with ethylenediamine (0.1 mL) in methanol (0.2 mL). Thesolvent was removed in vacuo. The desired product was obtained viapreparative-HPLC/MS (C18 column eluting with a gradient of ACN/H₂Ocontaining 0.15% NH₄OH) (5.3 mg, 38%).

¹H NMR (400 MHz, CDCl₃): δ 10.25 (br s, 1H), 8.90 (s, 1H), 8.00 (s, 1H),7.50 (d, 1H), 7.06 (d, 1H), 3.36-3.28 (m, 1H), 2.98 (dd, 1H), 2.90 (dd,1H), 2.51-2.38 (m, 1H), 2.08-1.96 (m, 1H), 1.80-1.51 (m, 5H), 1.44-1.30(m, 2H); MS(ES):308 (M+1).

The following compound of Table 5d was also prepared as a racemicmixture, according to the procedure of the above Example 87.

TABLE 5d Ex. MS (ES) No. Structure Name R (M + 1) 88

3-[5-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)- 1,3-oxazol-2-yl]-hexanenitrile Pr 282

Example 90:5-(Methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile

Step 1. (2E)-5-(Methylthio)pent-2-enenitrile

To a 0° C. mixture of [chloro(triphenyl)phosphoranyl]ACN (2.5 g, 0.0073mol) in THF (10 mL, 0.1 mol) was added TEA (2.0 mL, 0.014 mol), and theresulting mixture was stirred for 30 min. The ice bath was removed for30 min, then the mixture was re-cooled back to 0° C., A solution of3-(methylthio)-propanol (0.68 mL, 0.0072 mol) in THF (1 mL, 0.02 mol)was added and the mixture was stirred overnight. Water was added and themixture was filtered. The filtrate was washed with water ×3 and brine.The organic phase was dried and the solvent was removed by rotaryevaporation to give 2.1 g of an off-white solid. The solid wastriturated with MTBE and was filtered. The filtrate was washed with 1NHCl, water, sat. NaHCO₃ and brine. The organic phase was dried and wasconcentrated using a rotary evaporator to give 0.62 g orange oil (44%yield, trans: cis˜2:1).

¹H NMR for trans (400 MHz, CDCl₃): δ 6.68 (1H, m); 5.14 (1H, d); 2.6(2H, m); 2.55 (2H, t); 2.1 (3H, s).

Step 2.5-(Methylthio)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile

A mixture of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(0.30 g, 0.00095 mol), (2E)-5-(methylthio)pent-2-enenitrile (0.28 g,0.0016 mol) and DBU (45 μL, 0.00030 mol) in ACN (3 mL, 0.06 mol) wasstirred at rt for 5 days. The solvent was removed by rotary evaporationto give an orange oil. The crude oil was chromatographed with 30-70ethyl acetate/hex, to give 0.35 g of a colorless oil (83% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.95 (1H, s); 8.41 (1H, s); 8.4 (1H, s); 7.48(1H, d); 6.84 (1H, d); 5.75 (2H, s); 4.95 (1H, br); 3.6 (2H, t); 3.1(2H, m); 2.58 (2H, m); 2.28 (2H, m); 2.1 (3H, s); 1.99 (2H, t); 0.0 (9H,s). MS (M+H)⁺: 443.

Step 3.5-(Methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile

A solution of5-(methylthio)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile(0.35 g, 0.00079 mol) in THF (4 mL, 0.05 mol) and 3.0 M HCl (HCl) inwater (4 mL) was heated to reflux overnight. The solvent was removed byrotary evaporation to give a pale orange oil. The oil was stirred inethanol (3 mL, 0.05 mol) and 8.0 M ammonium hydroxide in water (1 mL)overnight. The reaction was concentrated and purified by prep LCMS (C18column eluting with a gradient of ACN/H₂O containing 0.15% NH₄OH) togive 125 mg of a white foam. The white foam was triturated with MTBE(˜1.5 mL). The resulting solid was filtered, washed and dried to give 80mg of the product (32% yield).

¹H NMR (400 MHz, CDCl₃): δ 10.38 (1H, s); 8.88 (1H, s); 8.39 (1H, s);8.38 (1H, s); 7.44 (1H, d); 6.8 (1H, d); 5.75 (2H, s); 4.9 (1H, br);3.05 (2H, m); 2.5 (2H, m); 2.23 (2H, d); 2.1 (3H, s). MS (M+H): 313.

Example 91:5-(Methylsulfinyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanenitrile

A solution of5-(methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanenitrile(0.065 g, 0.00021 mol) and hydrogen peroxide (0.022 mL, 0.00023 mol) inACN (1 mL, 0.02 mol) was stirred overnight. The reaction wasconcentrated and purified by HPLC to give 21 mg of a solid. The solidwas triturated with MTBE (1 mL)/DCM (10 drops). The solid was filteredand washed to give 13 mg of a white solid (20% yield) which was dried rtto 50° C. for 2 h.

¹H NMR (400 MHz, CDCl₃): δ 9.95 (1H, s); 8.85 (1H, s); 8.4 (2H, m); 7.4(1H, d); 6.8 (1H, s); 4.9 (1H, br); 3.15 (2H, m); 3.0 (2H, m); 2.8-2.5(2H, m); 2.6 (3H, s). MS (M+H): 329.

Example 92:5-(Methylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanenitrile

A solution of5-(methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanenitrile(0.040 g, 0.00013 mol) and hydrogen peroxide (0.5 mL, 0.005 mol) in ACN(1 mL, 0.02 mol) was refluxed overnight. The reaction was purified byHPLC to give 16 mg of a white glass/solid which was triturated with EtOH(˜0.8 mL) to give 13 mg of a white solid (30% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.75 (1H, s); 8.48 (1H, d); 8.4 (1H, d); 7.43(1H, d); 6.8 (1H, s); 5.0 (1H, br); 3.4 (2H, m); 3.2-3.0 (2H, m);2.8-2.5 (2H, m); 2.95 (3H, s). MS (M+H): 345.

Example 93:4,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrazol-1-yl]-butyronitrile

Step 1.4,4,4-Trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]butanenitrile

A mixture of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(6.9 g, 0.022 mol), (2E)-4,4,4-trifluorobut-2-enenitrile (2.8 g, 0.023mol) and DBU (0.18 mL, 0.0012 mol) in ACN (70 mL, 1 mol) was stirred for20 min. The reaction was filtered and filtrate was removed by rotaryevaporation to give an orange oil. The crude oil was chromatographedwith 20-50% ethyl acetate/hex to give to give 9.1 g of a solid/oil (96%yield). A single enantiomer (peak 2) was separated by chiral columnchromatography (OD-H column, 30% EtOH/hex) as a greenish solid/glass(3.3 g, 32% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.93 (1H, s); 8.46 (1H, s); 8.45 (1H, s); 7.5(1H, d); 6.85 (1H, d); 5.75 (2H, s); 5.2 (1H, m); 3.6 (2H, t); 3.7-3.3(2H, m); 1.99 (2H, t); 0.0 (9H, s). MS (M+H): 438.

Step 2.4,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrazol-1-yl]-butyronitrile

A solution of4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile(3.1 g, 0.0071 mol) from Step 1 in THF (35 mL, 0.43 mol) and 3.0 M HClin water (35 mL) was heated to reflux overnight. The solvent was removedby rotary evaporation to give a greenish orange oil/glass. The oil wasstirred with ethyl acetate and sat. NaHCO₃ (50 mL). The aqueous phasewas extracted with ethyl acetate. The organic layers were washed withbrine and reduced by rotary evaporation to give an oil/glass residue.The residue was stirred in ethanol (20 mL, 0.3 mol) and 8.0 M ammoniumhydroxide in water (10 mL) over a weekend. The solvent was removed byrotary evaporation to give a pale orange foam/solid. The crude waschromatographed with 0-7% MeOH/DCM, 0-0.7% NH4OH to give 3 g of a paleorange paste/solid. The solid was recrystallized from EtOH to give 1.6 gof an off-white crystals (74% yield).

¹H NMR (400 MHz, DMSO): δ 12.2 (1H, s); 8.95 (1H, s); 8.7 (1H, s); 8.5(1H, s); 7.63 (1H, d); 6.96 (1H, d); 6.01 (1H, m); 3.7 (2H, m). MS(M+H): 306.

The following compounds of Table 5e were prepared as indicated in thecolumn labeled 5 “Prep. Ex. No.”

TABLE 5e Ex. MS Prep. No. Structure Name (M + H) Ex. No. 94

5,5-Dimethyl-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-pyrazol-1-yl]-hexanenitrile 308 61 modification G 95

4-[1-(2-Methanesulfonyl-ethyl)- 1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine 291 61 modification G 96

5,5,5-Trifluoro-4-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-pyrazol-1-yl]-pentanenitrile 320 59 modification G

Example 97:3-(2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)-cyclo-pentane-carbonitriletrifluoroacetate

Step 1: 3-(Dimethoxymethyl)cyclopentanecarbaldehyde

Into a 3-neck round bottom flask 2-norbornene (5.500 g, 0.05841 mol) wasdissolved in DCM (198.0 mL,) and methanol (38.5 mL) and was cooled at−78° C. Ozone was passed through the reaction until it turned blue andwas stirred at −78° C. for 30 minutes. Then nitrogen was passed throughfor 20 minutes and p-toluenesulfonic acid (0.95 g, 0.0055 mol) was addedThe reaction was allowed to warm at 20° C. and was stirred for 90minutes. Into the reaction was added sodium bicarbonate (1.67 g, 0.0199mol) and the resulting mixture was stirred at 20° C. for 30 minutes anddimethyl sulfide (9.4 mL, 0.13 mol) was added. The reaction was stirredfor 16 hours and was reduced by rotary evaporation to −50 mL Thereaction was extracted with DCM and the organic extracts were washedwith water and brine, dried (MgSO₄), and stripped in vacuo. The reactionwas distilled at 135° C. (bath temperature) at high pump vacuum to givethe product (7.5 g) as a −2:1 mixture of diastereomers. ¹H NMR (300 MHz,CDCl₃): 9.64 & 9.62 (d, 1H), 4.15 & 4.12 (s, 1H), 3.35 & 3.34 (s, 6H),2.77 m, 1H), 2.34 (m, 1H), 1.35-2.00 (m, 6H).

Step 2. (2E, Z)-3-[3-(Dimethoxymethyl)cyclopentyl]acrylonitrile

Into a flask containing a 0° C. solution of t-BuOK in THF (1.0 M, 6.10mL) was added a solution of diethyl cyanomethylphosphonate (1.1 g, 6.4mmol) in THF (8 mL). The cooling bath was removed and the reaction waswarmed to ambient temperature, then a solution of3-(dimethoxy-methyl)cyclopentanecarbaldehyde (1.00 g, 5.81 mmol) in THF(2 mL) was added dropwise. Shortly after completion of the additionorange gel-like particulates began to form, after approximately 1 hourthe reaction was gelatinous. The reaction was held with stirring atambient temperature for 16 hours at which time tlc indicated completereaction. The reaction was partitioned between water and EtOAc and theaqueous phase was washed with additional EtOAc. The combined organicphase was washed with water, then sat'd NaCl, and then was dried overMgSO₄ and reduced in vacuo, and the resulting residue was purified bycolumn chromatography with 6:1 hexanes:EtOAc+1% TEA to obtain theproduct as a 1:1 mixture of E/Z isomers (760 mg, 61%). ¹H NMR (400 MHz,CDCl₃): δ vinylic protons at 6.69 (m, 0.5H), 6.37 (m, 0.5H), 5.32 (m,0.5H), 5.23 (m, 0.5H), acetal methine proton at 4.14 (m, 1H), methylprotons at 3.34 (s, 6H).

Step 3.3-[3-(Dimethoxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(230 mg, 0.74 mmol) in ACN (5 mL) was added(2E,Z)-3-[3-(dimethoxymethyl)cyclopentyl]acrylonitrile (289 mg, 1.48mmol), followed by DBU (300 μL, 2.0 mmol). The mixture was stirred atambient temperature for 16 hours, at which point LCMS and TLC indicatedcomplete reaction. The reaction was reduced to dryness in vacuo, and theresidue was purified by column chromatography to obtain the product as amixture of diastereomers (293 mg, 77%). ¹H NMR (400 MHz, CDCl₃): δ 8.85(s, 1H), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.28(m, 1H), 4.11 (m, 1H), 3.54 (t, 2H), 3.36 (s, 1.5H), 3.34 (s, 1.5H),3.30 (s, 1.5H), 3.26 (s, 1.5H), 3.12 (m, 1H), 2.94 (m, 1H), 2.65 (m,1H), 2.34 (m, 1H), 2.0-1.0 (m, 6H), 0.92 (t, 2H), −0.56 (s, 9H). MS (EI)m/z=511.3 (M+H).

Step 4.3-(3-Formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

To a solution of3-[3-(dimethoxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(293 mg, 0.574 mmol) in THF (4.5 mL) was added aqueous HCl (1.0 M, 1.5mL). The reaction was held at ambient temperature for 2.5 hours at whichpoint TLC and LCMS indicated complete deprotection to the correspondingaldehyde. The reaction was partitioned between water and EtOAc and theaqueous phase was extracted with additional EtOAc. The combined organicphase was washed with water, then sat'd NaHCO₃, then sat'd NaCl, andthen was dried over MgSO₄ and filtered and stripped to dryness to leavethe crude product as a mixture of diastereomers. ¹H NMR (400 MHz,CDCl₃): δ 9.69 (d, 0.5H), 9.64 (d, 0.5H), 8.85 (s, 0.5H), 8.84 (s,0.5H), 8.35 (s, 0.5H), 8.34 (s, 0.5H), 8.32 (s, 0.5H), 8.30 (s, 0.5H),7.41 (d, 0.5H), 7.40 (d, 0.5H), 6.80 (d, 0.5H), 6.79 (d, 0.5H), 5.68 (s,1H), 5.67 (s, 1H), 4.32 (m, 1H), 3.54 (m, 2H), 3.14 (m, 1H), 2.96 (m,2H), 2.76 (m, 1H), 2.1-1.1 (m, 6H), 0.92 (m, 2H), −0.058 (s, 9H). MS(EI) m/z=465.1 (M+H).

Step 5.3-3-[(E,Z)-(Hydroxyimino)methyl]cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

To a solution of3-(3-formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(336 mg, 0.000723 mol) in CH₃OH (5.0 mL, 0.12 mol) was addedhydroxylamine hydrochloride (60 mg, 0.00087 mol) and KHCO₃ (110 mg,0.0011 mol) and the reaction was held at ambient temperature for 16hours, at which point LCMS indicated complete reaction. The reaction wasreduced to dryness in vacuo and the residue was partitioned betweenwater and EtOAc, and the aqueous phase was extracted with additionalEtOAc. The combined organic phase was washed with water, then sat'dNaCl, then was dried over MgSO₄ and concentrated to leave the crudeproduct, which was carried forward to the subsequent reaction withoutpurification. NMR indicated disappearance of aldehydic protons. MS (EI)m/z=480.2 (M+H).

Step 6.3-(2-Cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]ethyl)cyclopentanecarbonitrile

To a solution of3-3-[(E,Z)-(hydroxyimino)methyl]cyclopentyl-3-[4-(7-[2-(trimethylsilyl)-ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(324 mg, 0.67 mmol) in pyridine (1.2 mL), was added methanesulfonylchloride (210 μL, 2.7 mmol) dropwise. The reaction was heated to 60° C.for 2.5 hours, at which point LCMS indicated complete reaction. Thereaction was partitioned between water and EtOAc, and the aqueous phasewas extracted with additional EtOAc. The combined organic phase waswashed with water, then 0.1N HCl, then sat'd NaCl, and then was driedover MgSO₄. The crude product was purified by column chromatography toobtain the product as a mixture of diastereomers (164 mg, 52%). Thediastereomers were then separated by chiral HPLC to provide fourdistinct diastereomers, which were taken directly on to the deprotectionstep. MS (EI) m/z=462.1 (M+H).

Step 7.3-(2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]ethyl)-cyclopentanecarbonitriletrifluoroacetate

The four diastereomers were then separately deprotected in thisrepresentative manner. To3-2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylcyclopentanecarbonitrile(35 mg, 0.076 mmol) dissolved in CH₂Cl₂ (2.0 mL) was added TFA (1.0 mL)and the reaction was stirred for 2 hours at ambient temperature at whichpoint LCMS indicated complete cleavage to the N-hydroxymethylintermediate. The solvent was removed and to the residue was addedmethanol (1.0 mL) followed by ethylenediamine (40 μL, 0.61 mmol), thereaction was stirred for 16 hours at which point LCMS indicated completereaction. The solvent was removed and the residue was purified bypreparative LCMS to provide the product as a TFA salt. NOE experimentsconfirm that all isomers have cis geometry on cyclopentyl ring. Isomers1 and 2:

¹H NMR (400 MHz, CD₃OD): δ 8.95 (s, 1H), 8.89 (s, 1H), 8.54 (s, 1H),7.86 (d, 1H), 7.29 (d, 1H), 4.72 (m, 1H), 3.27 (m, 1H), 3.19 (m, 1H),2.95 (m, 1H), 2.72 (m, 1H), 2.2-1.9 (m, 4H), 1.67 (m, 2H).

Isomers 3 and 4: ¹H NMR (400 MHz, CD₃OD): δ 8.95 (s, 1H), 8.88 (s, 1H),8.52 (s, 1H), 7.85 (d, 1H), 7.28 (d, 1H), 4.72 (m, 1H), 3.27 (m, 1H),3.19 (m, 1H), 3.05 (m, 1H), 2.71 (m, 1H), 2.44 (m, 1H), 2.05 (m, 1H),1.92 (m, 1H), 1.72 (m, 1H), 1.58 (m, 2H). MS (EI) m/z=332.2 (M+H).

Example 98:3-[3-(Hydroxymethyl)cyclopentyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

Step 1:3-[3-(Hydroxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]propanenitrile

A solution of3-(3-formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(50.0 mg, 0.108 mmol) in methanol (280 μL) was cooled to 0° C., thensodium tetrahydroborate (14 mg, 0.37 mmol) was added. The reaction washeld at 0° C. for 10 minutes, at which point LCMS and TLC indicatedcomplete reaction. The reaction was quenched by cautious addition of 1NHCl (3 drops) and methanol (1 mL), followed by addition of aqueousNaHCO₃ and CHCl₃. The phases were separated and the aqueous phase waswashed with additional CHCl₃. The combined organic phase was washed withsat'd NaCl, dried over MgSO₄ and reduced to dryness. The residue waspurified by column chromatography to obtain the product as a mixture ofdiastereomers (37.4 mg, 74%). ¹H NMR (400 MHz, CDCl₃): δ 8.84 (s, 1H),8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.29 (m, 1H),3.53 (m, 1H), 3.53 (t, 2H), 3.14 (m, 1H), 2.95 (m, 1H), 2.68 (m, 1H),2.2-1.0 (m, 9H), 0.92 (t, 2H), −0.059 (s, 9H). MS (EI) m/z=467.2 (M+H).

Step 2.3-[3-(Hydroxymethyl)cyclopentyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]propanenitrile

To3-[3-(hydroxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(60.4 mg, 0.129 mmol) dissolved in CH₂Cl₂ (2.0 mL) was added TFA (1.0mL) and the reaction was stirred for 1 hour at which point LCMSindicated complete cleavage to the N-hydroxymethyl intermediate(m/z=367). The trifluoroacetate ester of the hydroxymethyl of thecyclopentyl ring was also observed (m/z=463). The solvent was removedand to the residue was added methanol (1.0 mL) followed byethylenediamine (80 μL, 1.19 mmol). The resulting mixture was stirredfor 16 hours at which point LCMS indicated complete reaction to thedesired product. The solvent was removed and the residue was purified bychiral HPLC to provide four distinct diastereomers (20.2 mg total offour isomers, 46%). NOE experiments suggest that all isomers have cisgeometry on the cyclopentyl ring. Isomers 1 and 2: ¹H NMR (400 MHz,CD₃OD): δ 8.65 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 7.50 (d, 1H), 6.95(d, 1H), 4.51 (m, 1H), 3.40 (m, 2H), 3.22 (m, 1H), 3.11 (m, 1H), 2.61(m, 1H), 2.10 (m, 1H), 1.94 (m, 1H), 1.82 (m, 1H), 1.6-1.4 (m, 3H), 1.03(m, 1H). Isomers 3 and 4: ¹H NMR (400 MHz, CD₃OD): δ 8.66 (s, 1H), 8.62(s, 1H), 8.37 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.46(m, 2H), 3.21 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.22 (m, 1H), 2.09(m, 1H), 1.71 (m, 1H), 1.55-1.25 (m, 3H), 1.04 (m, 1H). MS (EI)m/z=337.1 (M+H).

Example 100: 1-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole (100a) and2-(1H-pyrrolo[2,3-b]-pyridin-4-yl)-2H-indazole (100b)

4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.078 g, 0.00040 mol) and 1H-indazole(0.283 g, 0.00240 mol) was heated neat in a sealed tube at 200° C. (anoil bath) overnight with stirring. The reaction was allowed to cool tort and the crude product was purified by prep LC-MS on a C-18 columneluting with a water/ACN gradient containing 0.2% TFA to give the titlecompound (0.015 gm, 15%), as an amorphous white solid, LC/MS (M+H)⁺235,¹H NMR (DMSO-d₆) δ 12.01 (bs, 1H), 9.17 (s, 1H), 8.31 (s, 1H), 7.73 (d,1H, J=9.0), 7.67 (m, 2H), 7.58 (m, 1H), 7.28 (m, 1H), 7.07 (m, 2H).

Example 106:3-[3-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxadiazol-5-yl]benzonitrile

Step 1.1-[2-Ttrimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.300 g, 0.000917 mol) was dissolved in DMF (6.5 mL, 0.084 mol) andthen zinc cyanide (0.30 g, 0.0026 mol) was added. The solution wasdegassed with nitrogen and then bis(tri-t-butylphosphine)palladium (0.1g, 0.0002 mol) was added. The reaction was sealed and heated in themicrowave to 100° C. for 30 minutes. The reaction was allowed to cool tort, taken up in ethyl acetate and washed with water saturated sodiumcarbonate, brine, dried over magnesium sulfate and concentrated to givean oil. The crude product was purified by flash column chromatography(FCC) on silica gel, eluting with a hexane: ethyl acetate gradient togive the product (0.25 gm) as a colorless oil. LC/M S (M+H)⁺274, ¹H NMR(CDCl₃) δ 8.22 (d, 1H), 7.53 (d, 1H), 7.40 (d, 1H), 6.73 (d, 1H), 5.65(s, 2H), 3.50 (m, 2H), 0.90 (m, 2H), 0.0 (s, 9H).

Step 2.N-Hydroxy-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine-4-carboximidamide

1-[2-(Trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile(0.05 g, 0.0002 mol) was dissolved in ethanol (2.0 mL, 0.034 mol), andthen hydroxylamine hydrochloride (0.023 g, 0.00033 mol) and potassiumcarbonate (0.10 g, 0.00073 mol) were added. The reaction was heated toreflux for 5 h, and the reaction was then allowed to cool to rt andfiltered to remove the solids. The filtrate was concentrated to give theproduct 0.06 g as yellow oily residue, LC/MS (M+H)⁺307.

Step 3.3-[3-(1-[2-(Trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxadiazol-5-yl]benzonitrile

The crude productN-hydroxy-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine-4-carboximidamide(0.06 gm, 0.0002 mol) was dissolved in pyridine (1.0 mL, 0.012 mol) andthen 3-cyanobenzoyl chloride (0.040 g, 0.00024 mol) was added at rt.This mixture was stirred for 1 h and heated to 80° C. in an oil bath.After heating for 18 h the reaction was allowed to cool to rt and thendiluted with ACN and concentrated in vacuo to give3-[3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxadiazol-5-yl]benzonitrile0.08 gm as an off white residue, LC/M S (M+H)⁺418.

Step 4.3-[3-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxadiazol-5-yl]benzonitrile

The crude3-[3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxadiazol-5-yl]benzonitrile(0.08 g, 0.0002 mol) was dissolved in TFA (3.0 mL, 0.039 mol) undernitrogen and then heated to 60° C. After heating for 2 h the reactionwas allowed to cool to rt and concentrated in vacuo. The resultingresidue was taken up in methanol and concentrated to remove as much ofthe TFA as possible. The residue was taken up in methanol (2.0 mL, 0.049mol) and ammonium hydroxide (1 mL). This mixture was stirred at rt for 2h and the reaction was then complete. The reaction was concentrated invacuo to give the crude product which was purified by prep HPLC on aC-18 column eluting with a ACN:water gradient with 0.2% TFA to give thetitle compound (0.025 gm, 43%) (M+H)⁺288. ¹H NMR (DMSO-d₆) δ 12.1 (bs,1H), 8.65 (s, 1H), 8.48 (d, 1H, J=6.4), 8.39 (d, 1H, J=4.8), 8.16 (d,1H, J=6.4), 7.84 (t, 1H, J=6.4), 7.75 (d, 1H, J=4.8), 7.68 (m, 1H), 6.99(m, 1H).

Example 107: 4-(1-Benzothien-2-yl)-1H-pyrrolo[2,3-b]pyridine

Step 1.4-(1-Benzothien-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

1-Benzothien-2-ylboronic acid (0.05 g, 0.0003 mol) and4-bromo-1-[2-(trimethylsilyl)-ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.10 g, 0.00031 mol) were combined in toluene (3.0 mL, 0.028 mol) andethanol (1.0 mL, 0.017 mol). Potassium carbonate (0.085 g, 0.00062 mol)dissolved in water (1.0 mL) then was added and the reaction was degassedwith nitrogen. Then tetrakis(triphenylphosphine)palladium(0) (0.05 g,0.00004 mol) was added and the reaction was heated to 120° C. in asealed tube in the microwave for 60 minutes. This was allowed to cool tort, taken up in ethyl acetate and washed with water 2×, brine, driedover magnesium sulfate and concentrated to give4-(1-benzothien-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridine(0.10 gm) as an oil, LC/MS (M+H)⁺381.

Step 2. 4-(1-Benzothien-2-yl)-1H-pyrrolo[2,3-b]pyridine

Using a procedure analogous to Example 106, Step 4, but using4-(1-benzothien-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine,the title compound was prepared as a yellow powder (0.015 g, 18%), LC/MS(M+H)⁺: 251, ¹H NMR (DMSO-d₆) δ 11.95 (bs, 1H), 8.28 (d, 1H, J=5.4),8.15 (s, 1H), 8.03 (m, 1H), 7.96 (m, 1H), 7.64 (m, 1H), 7.42 (m, 2H),7.39 (d, 1H, J=5.4), 6.95 (m, 1H).

Example 120:4-Fluoro-2-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]phenol

4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00025 mol) and4-fluoro-2-(1H-pyrazol-3-yl)phenol (0.150 g, 0.000842 mol) were heatedneat to 160° C. for 5 h. The reaction was allowed to cool to rt and theresidue was purified by prep LC-MS on a C-18 column eluting with awater/ACN gradient containing 0.2% TFA to give the title compound,(0.052 g, 20%, as an amorphous white solid, LC/MS (M+H)⁺295, ¹H NMR(DMSO-d₆) δ 12.01 (bs, 1H), 10.25 (bs, 1H), 8.81 (s, 1H), 8.35 (d, 1H,J=5.5), 7.77 (d, 1H, J=9.5), 7.64 (m, 1H), 7.59 (d, 1H, J=5.5), 7.32 (s,1H), 7.09 (m, 1H), 7.05 (m, 1H), 7.01 (m, 1H).

Example 127:4-3-[3-(Trifluoromethyl)phenyl]-1H-pyrazol-1-yl-1H-pyrrolo[2,3-b]pyridine

Step 1.(2E)-3-(Dimethylamino)-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one

1-[5-(Trifluoromethyl)phenyl]ethanone (0.20 mL, 0.0013 mol) and1,1-dimethoxy-N,N-dimethylmethanamine (0.17 mL, 0.0013 mol) werecombined in a sealed tube and heated in a microwave to 120° C. for 15minutes, the reaction was allowed to cool and was concentrated to removethe residual DMF acetal, to give(2E)-3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one,0.32 gm, as a red oil, LC/MS (M+H)⁺: 244.

Step 2: 3-[3-(Trifluoromethyl)phenyl]-1H-pyrazole

The (2E)-3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one(0.32 g, 0.0013 mol) was dissolved in ethanol (10.0 mL, 0.171 mol) andhydrazine (0.24 mL, 0.0078 mol) under nitrogen and heated to reflux. Thereaction was monitored by HPLC and was complete almost immediately. Themixture was allowed to cool to rt and concentrated to give the crudeproduct as an oil. The product was purified by FCC on silica gel elutingwith a hexane: ethyl acetate gradient to give3-[3-(trifluoromethyl)phenyl]-1H-pyrazole as an oil (0.25 g, 89%), LC/MS(M+H)⁺: 213, ¹H NMR (CDCl₃) δ 8.06 (s, 1H), 7.99 (d, 1H, J=7.5), 7.66(d, 1H, J=2.4), 7.57 (m, 1H), 7.55 (d, 1H, J=7.5), 6.69 (d, 1H, J=2.4).

Step 3.4-3-[3-(Trifluoromethyl)phenyl]-1H-pyrazol-1-yl-1H-pyrrolo[2,3-b]pyridine

4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.028 g, 0.00014 mol) and3-[3-(trifluoromethyl)-phenyl]-1H-pyrazole (0.03 g, 0.0001 mol) werecombined neat. The reaction was heated in a sealed tube in an oil bathto 175° C. for 20 to produce a crude product that was a black viscousgum. The crude product was purified by HPLC on a C-18 column elutingwith a water:ACN gradient with 0.2% TFA to give the title product (0.025gm, 50%) as a white amorphous solid, LC/MS (M+H)⁺: 329, ¹H NMR (DMSO-d₆)δ 11.95 (bs, 1H), 8.83 (d, 1H, J=2.7), 8.31 (m, 3H), 7.75 (m, 2H), 7.60(m, 2H), 7.35 (d, 1H, J=2.7), 7.14 (m, 1H).

Example 128:3-[1-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]benzonitrile

Step 1. 3-[(2E)-3-(Dimethylamino)prop-2-enoyl]benzonitrile

3-Acetylbenzonitrile (0.435 g, 0.00300 mol) and1,1-dimethoxy-N,N-dimethylmethanamine (0.400 mL, 0.00301 mol) werecombined and heated in sealed tube to 120° C. in the microwave for 15min. The reaction was then allowed to cool to rt giving the3-[(2E)-3-(dimethylamino)prop-2-enoyl]-benzonitrile as a red-orangecrystalline material, LC/MS (M+H)⁺: 201.

Step 2. 3-(1H-Pyrazol-3-yl)benzonitrile

The 3-[(2E)-3-(dimethylamino)prop-2-enoyl]benzonitrile (0.600 g, 0.00300mol) was dissolved in ethanol (20.0 mL, 0.342 mol) and hydrazine (0.56mL, 0.018 mol) under an atmosphere of nitrogen was stirred at roomtemperature for 1.5 h. The reaction was concentrated in vacuo to give adark product which was purified by FCC on silica gel, eluting with ethylacetate-hexane 1:1 to give 3-(1H-pyrazol-3-yl)benzonitrile as an oil(0.430 g, 84%), LC/MS (M+H)⁺: 170.

Step 3.3-[1-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]benzonitrile

4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.075 g, 0.00038 mol) and3-(1H-pyrazol-3-yl)benzonitrile (0.161 g, 0.000952 mol) were heated insealed tube to 160° C. for 18 h. The resulting product, dark viscousgum, was purified by HPLC on a C-18 column eluting with a water:ACNgradient with 0.2% TFA to give the title product (0.030 g, 27%) as awhite amorphous solid, LC/MS (M+H)⁺: 286, ¹H NMR (DMSO-d₆) δ 11.95 (bs,1H), 8.76 (s, 1H), 8.36 (s, 1H), 8.29 (d, 1H, J=7.5), 8.25 (d, 1H,J=5.0), 7.79 (d, 1H, J=7.5), 7.62 (t, 1H, J=7.5), 7.53 (m, 2H), 7.25 (s,1H), 7.11 (m, 1H).

Example 153:3-[1-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]benzonitrile

Step 1.4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazole

A solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g,0.010 mol) and DMF (30.0 mL, 0.387 mol) was cooled to 0° C. Sodiumhydride (320 mg, 0.013 mol) (60% in oil) was added and the mixture wasstirred for 10 min. [β-(Trimethylsilyl)ethoxy]methyl chloride (2.4 mL,0.013 mol) was added and the resulting mixture was stirred for 20 min at0° C. and 2 h at room temperature. The reaction was partitioned betweenwater and ethyl acetate. The organic layer was washed with brine, driedover MgSO₄ and concentrated to give4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazoleas a crude material. LC/MS (M+H)⁺: 325, ¹H NMR (CDCl₃) δ 7.85 (s, 1H),7.80 (s, 1H), 5.45 (s, 2H), 3.55 (t, 2H), 1.35 (s, 12H), 0.95 (t, 2H),0.0 (s, 9H).

Step 2.3-(1-[2-(Trimethylsilyl)ethoxy]methyl-1H-pyrazol-4-yl)benzonitrile

A mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrazole(150.0 mg, 0.0004625 mol) and 3-bromobenzonitrile (0.10 g, 0.00056 mol)in toluene (2.0 mL, 0.019 mol) and ethanol (0.3 mL, 0.005 mol) wastreated with sodium carbonate (98 mg, 0.00092 mol) in water (0.5 mL,0.03 mol). The mixture was degassed by bubbling nitrogen.Tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.000046 mol) was addedand nitrogen was bubbled for 3 min. The reaction was heated in amicrowave at 80° C. for 30 min, then allowed to cool to rt and taken upin water and ethyl acetate. The organic layer was dried over MgSO₄,filtered and concentrated to give a crude product, which was purified byFCC on silica gel, eluting with EtOAc/Hexanes (1:5) to give3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazol-4-yl)benzonitrile, asan oil, LC/MS (M+H)⁺: 300.

Step 3. 3-(1H-Pyrazol-4-yl)benzonitrile trifluoroacetate

A solution of3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazol-4-yl)benzonitrile(110.0 mg, 0.0003673 mol) was taken up in TFA (3.0 mL, 0.039 mol) andthe mixture was heated in microwave at 120° C. for 3 min. The reactionmixture was allowed to cool to rt, and then concentrated to give a cruderesidue. The product was purified by HPLC on a C-18 column eluting witha water/ACN gradient containing 0.2% TFA to give3-(1H-pyrazol-4-yl)benzonitrile trifluoroacetate as an amorphous whitesolid, LC/MS (M+H)⁺: 170.

Step 4.3-[1-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]benzonitrile

A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (25.0 mg, 0.000127 mol)and 3-(1H-pyrazol-4-yl)benzonitrile trifluoroacetate (23.6 mg, 0.0000833mol) was heated at 180° C., neat overnight. The crude residue waspurified by HPLC on a C-18 column eluting with a water; ACN gradientcontaining 0.2% TFA to give the title compound as an amorphous whitesolid, LC/MS (M+H)⁺: 286, ¹H NMR (DMSO-d₆) δ 11.85 (bs, 1H), 9.18 (s,1H), 8.42 (s, 1H), 8.28 (s, 1H), 8.25 (d, 1H, J=5.0), 8.07 (d, 1H,J=7.0), 7.64 (d, 1H, J=7.0), 7.56 (t, 1H, J=7.0), 7.51 (m, 1H), 7.47 (d,1H, J=5.0), 7.03 (m, 1H).

Example 170:2-[1-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-1,3-benzoxazole

Step 1.4-Hydrazino-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

To 4-bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(1.98 g, 0.00605 mol) was added hydrazine (11.0 mL, 0.350 mol) followedby addition of methanol (1.0 mL, 0.025 mol) (to improve solubility). Thereaction mixture was heated in a sealed tube at 97° C. (an oil bath) for18 h. The reaction mixture was cooled to rt and formed an off-whitesolid precipitate. The solid was filtered off and rinsed with cold waterand dried to give4-hydrazino-1-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine(1.55 gm) as a light yellow solid, LC/MS (M+H)⁺:279, ¹H NMR (DMSO-d₆) δ7.98 (d, 1H), 7.91 (s, 1H), 7.28 (d, 1H), 6.69 (s, 1H), 6.61 (d, 1H),5.58 (s, 2H), 4.37 (s, 2H), 3.56 (t, 2H), 0.90 (t, 2H), 0.0 (s, 9H).

Step 2.2-[1-(1-[2-(Trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-1,3-benzoxazole

To4-hydrazino-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.083 g, 0.00030 mol) 3782-117-1 and 1,3-benzoxazol-2-ylmalonaldehyde(0.056 g, 0.00030 mol) in toluene (1.5 mL, 0.014 mol) was addedmolecular sieves. The mixture was heated in a sealed tube at 70° C. (anoil bath) with stirring for 2 h. The solvent was removed in vacuo andthe crude product was purified by FCC on silica using ethylacetate:hexanes 3:7 to give2-[1-(1-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-1,3-benzoxazole(0.090 gm) as an oil, LC/MS (M+H)⁺: 432.

Step 3

Using a procedure analogous to Example 106, Step 4, but using2-[1-(1-[2-(trimethylsilyl)-ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-1,3-benzoxazole,the title compound was prepared as a white amorphous powder (0.015 gm,18%), LC/MS (M+H)⁺:302, ¹H NMR (DMSO-d₆) δ 11.85 (bs, 1H), 9.45 (s, 1H),8.53 (s, 1H), 8.36 (bs, 1H), 7.7-7.6 (m, 2H), 7.65 (d, 1H), 7.56 (bs,1H), 7.38-7.34 (m, 2H), 7.01 (d, 1H).

Example 172:Cyclohexyl[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]methanol

Step 1. 4-(4-Bromo-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine

A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.10 g, 0.00558 mol) and4-bromo-1H-pyrazole (1.2 g, 0.0084 mol) was heated neat to 150° C. for 2h. DMF was added to dissolve the crude residue. This residue was takenup in EtOAc and washed with 1N NaOH. The organic layer was washed withbrine, dried over MgSO₄, filtered and concentrated to give a crude4-(4-bromo-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine residue, LC/MS(M+H)⁺: 263, 265.

Step 2.4-(4-Bromo-1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

A solution of4-(4-bromo-1H-pyrazol-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl chloride(1.4 mL, 0.0079 mol) was added and stirred for 20 min at 0° C. Thereaction was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over MgSO₄ and concentrated to givethe crude material. The product was purified by FCC on silica gel(EtOAc/Hexanes, 1/10) to give4-(4-bromo-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridineas a solid product, LC/MS (M+H)⁺: 393, 394, ¹H NMR (CDCl₃) δ 8.47 (d,1H, J=7.0), 8.27 (s, 1H), 7.88 (s, 1H), 7.52 (d, 1H, J=4.5), 7.39 (d,1H, J=7.0), 7.069 (d, 1H, J=4.5), 5.80 (s, 2H), 3.6 (t, 2H), 1.95 (t,2H), 0.0 (s, 9H).

Step 3.Cyclohexyl[1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]methanol

A mixture of4-(4-bromo-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(50.0 mg, 0.000127 mol) in THF (2.0 mL, 0.025 mol) under a nitrogenatmosphere was cooled to −78° C. and 1.6 M n-butyllithium in water (1.00mL, 0.0555 mol). The mixture was stirred for 3 min. The reaction waspartitioned between water and EtOAc. The organic layer was dried overMgSO₄, filtered and concentrated to give the cyclohexyl[1-(1:5) to give4-yl)-1H-pyrazol-4-yl]methanol as a crude residue, LC/MS (M+H)⁺: 417.

Step 4. Cyclohexyl[1-phenylvinyl)-1H-pyrazol-4-yl]methanol

Using a procedure analogous to Example 106, Step 4, but usingcyclohexyl[1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine,the title compound was prepared as a white amorphous powder (0.015 gm,18%), LC/MS (M+H)⁺: 297. ¹H NMR (DMSO-d₆) δ 11.85 (bs, 1H), 8.44 (s,1H), 7.74 (s, 1H), 7.50 (m, 1H), 7.44 (d, 1H, J=6.5.70 (s, 1H), 5.37 (s,1H).

Example 173:4-[4-(1-Phenylvinyl)-1H-pyrazol-1-yl]-1H-pyrrolo[2,3-b]pyridine

Step 1.4-[4-(1-Phenylvinyl)-1H-pyrazol-1-yl]-1-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine

A mixture of (1-phenylvinyl)boronic acid (24.0 mg, 0.000162 mol) and4-(4-bromo-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(50.0 mg, 0.000127 mol) in toluene (2.00 mL, 0.0188 mol) and ethanol(0.50 mL, 0.0086 mol) was treated with potassium carbonate (35 mg,0.00025 mol) in water (1.00 mL, 0.0555 mol). The mixture was degassed bybubbling nitrogen. Tetrakis(triphenylphosphine)palladium(0) (10 mg,0.00001 mol) was added and nitrogen was bubbled for 3 min. The reactionwas heated in a sealed tube in the microwave at 100° C. for 30 min. Thereaction was allowed to cool to rt and partitioned between ethyl acetateand water. The combined organic layer was dried over MgSO₄, filtered andconcentrated to give the crude material The crude product was purifiedby FCC on silica gel eluting with EtOAc/Hexanes (1:5) to give4-[4-(1-phenylvinyl)-1H-pyrazol-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridineas a solid residue, LC/MS (M+H)⁺: 417.

Step 2

Using a procedure analogous to Example 106, Step 4, but using4-[4-(1-phenylvinyl)-1H-pyrazol-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine,the title compound was prepared as an white amorphous powder (0.015 gm,31%), LC/MS (M+H)⁺: 287, ¹H NMR (DMSO-d₆) δ 11.85 (bs, 1H), 8.63 (s,1H), 7.99 (s, 1H), 7.55 (bs, 1H), 7.48 (m, 2H), 7.43-7.37 (m, 5H), 7.01(m, 1H), 5.70 (s, 1H), 5.37 (s, 1H).

Example 200: 4-(1-Benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine

Step 1.4-(1-Benzyl-1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.100 g, 0.000306 mol) was combined with1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.113 g, 0.000398 mol) in toluene (3.0 mL, 0.028 mol) and ethanol (0.5mL, 0.008 mol). Potassium carbonate (0.084 g, 0.00061 mol) dissolved inwater (1.0 mL, 0.056 mol) was added and the reaction mixture wasdegassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.080g, 0.000069 mol) was added, and again the mixture was degassed withnitrogen for 5 min. The reaction was heated in sealed tube to 100° C. ina microwave for 30 minutes. The reaction was partitioned between ethylacetate and water. The organic layer was washed with water, brine, driedover magnesium sulfate and concentrated to give a crude residue. Theproduct was purified by FCC on silica gel using ethyl acetate:hexane3:7, to give4-(1-benzyl-1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine0.092 g as a semisolid residue, LC/MS (M+H)⁺: 405.

Step 2. 4-(1-Benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine

Using a procedure analogous to Example 106, Step 4, but using4-(1-benzyl-1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine,the title compound was prepared as a white amorphous powder (0.054 gm),LC/MS (M+H)⁺: 275, ¹H NMR (DMSO-d₆) δ 12.21 (bs, 1H), 8.80 (s, 1H), 8.25(vbs, 1H), 8.23 (s, 1H), 7.63 (s, 1H), 7.49 (bs, 1H), 7.4-7.2 (m, 5H),6.99 (s, 1H), 5.42 (s, 2H).

Example 201:4-[1-(2-Naphthylmethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine

Step 1.1-(2-Naphthylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.10 g,0.00052 mol) was combined with naphthalene, 2-(bromomethyl)-(0.12 g,0.00057 mol) in ACN (3.0 mL, 0.057 mol) under nitrogen at rt. Thencesium carbonate (0.50 g, 0.0015 mol) was added and the reaction wascomplete after stirring for 1 h. This was partitioned between ethylacetate and brine. The organic layer was washed with brine, dried overmagnesium sulfate and concentrated to give1-(2-naphthylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole0.17 gm, as an oil, LC/MS (M+H)⁺: 335, ¹H NMR (CDCl₃) δ 7.89 (s, 1H),7.79-7.84 (m, 3H), 7.69 (bs, 2H), 7.49-7.4 (m, 2H), 7.46-7.33 (m, 1H),5.47 (s, 2H), 1.31 (s, 12H).

Step 2.4-[1-(2-Naphthylmethyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.06 g, 0.0002 mol) and1-(2-naphthylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.074 g, 0.00022 mol) were combined in toluene (2.0 mL, 0.019 mol) andethanol (1.0 mL, 0.017 mol), and then potassium carbonate (0.063 g,0.00046 mol, in 1 mL water) was added. The reaction mixture was degassedwith nitrogen, then tetrakis(triphenylphosphine)palladium(0) (0.02 g,0.00002 mol) was added, sealed in a tube and heated to 120° C. in amicrowave for 30 minutes. This was allowed to cool and then partitionedbetween ethyl acetate and brine. The organic layer was dried overmagnesium sulfate and concentrated to give4-[1-(2-naphthylmethyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine0.08 g, as an oily residue, LC/MS (M+H)⁺: 455.

Step 3

Using a procedure analogous to Example 106, Step 4, but using4-[1-(2-naphthylmethyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine,the title compound was prepared as a white amorphous powder (0.053 g,88%), LC/MS (M+H)⁺: 325, ¹H NMR (DMSO-d₆) δ 12.0 (bs, 1H), 8.79 (s, 1H),8.24 (s, 1H), 8.19 (d, 1H, J=5.7), 7.82 (m, 4H), 7.56 (m, 1H), 7.43 (m,4H), 6.92 (m, 1H), 5.54 (s, 2H).

Example 219: 4-(1-Phenyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine

Step 1. 1-phenyl-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.07 g,0.0003 mol) and phenylboronic acid (0.083 g, 0.00068 mol) were combinedin DMF (1.50 mL, 0.0194 mol). Then copper(II) diacetate (0.010 g,0.000055 mol) and pyridine (0.069 mL, 0.00085 mol) were added. Thereaction was heated in an open tube to 80° C. for 40 minutes. Thereaction was complete by HPLC, allowed to cool to rt, taken up in ethylacetate, and washed with water saturated with sodium carbonate. Theorganic layer was washed with brine, dried over magnesium sulfate andconcentrated to give1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazo, 0.09gm as an oily residue, LC/MS (M+H)⁺: 271.

Step 2.4-(1-Phenyl-1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

Using a procedure analogous to Example 201, Steps B and C, but using1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazo, thetitle compound was prepared as an white amorphous powder (0.015 gm,18%), LC/MS (M+H)⁺: 261, ¹H NMR (DMSO-d₆) δ 12.05 (bs, 1H), 9.23 (s,1H), 8.53 (s, 1H), 8.31 (m, 1H), 8.01 (m, 2H), 7.63 (m, 1H), 7.57-7.52(m, 3H), 7.36 (m, 1H), 7.13 (m, 1H).

Example 231:3-[4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile

Step 1.4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine

4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.20 g, 0.00061 mol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.15 g,0.00079 mol) were combined in DMF (5.0 mL, 0.064 mol) and then potassiumcarbonate (0.25 g, 0.0018 mol) in 1 mL water was added. The reaction wasdegassed with nitrogen, then tetrakis(triphenylphosphine)-palladium(0)(0.08 g, 0.00007 mol) was added and in a sealed tube the reaction washeated to 120° C. oil bath. The reaction was heated for 30 minutes,allowed to cool and then taken up in ethyl acetate. The reaction mixturewas washed with brine, dried over magnesium sulfate and concentrated togive an oil. The product was purified by FCC on silica gel eluting witha hexane:ethyl acetate gradient to give4-(1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.13 gm, 70%) as a crystalline white powder, LC/MS (M+H)⁺: 315, ¹H NMR(DMSO-d₆) δ 13.35 (bs, 1H), 8.59 (bs, 1H), 8.32 (d, 1H, J=8.5), 8.26(bs, 1H), 7.76 (d, 1H, J=6.0), 7.45 (d, 1H, J=8.5), 7.01 (d, 1H, J=6.0),5.73 (s, 2H), 3.61 (t, 2H), 0.92 (t, 2H), 0.0 (s, 9H).

Step 2.3-[4-(1-[2-(Trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile

4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(0.025 g, 0.000080 mol) and (3-cyanophenyl)boronic acid (0.023 g,0.00016 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then copper(II)diacetate (0.002 g, 0.00001 mol) and pyridine (0.019 mL, 0.00024 mol)were added. The reaction was heated in an open tube to 125° C. for 40minutes, allowed to cool to rt, taken up in ethyl acetate, and washedwith water saturated with sodium carbonate. The organic layer was washedwith brine, dried over magnesium sulfate and concentrated to give3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-benzonitrile(0.025 gm, 92%) as an oily residue, LC/MS (M+H)⁺: 316.

Step 3

Using a procedure analogous to Example 106, Step 4, but using3-[4-(1-[2-(trimethylsilyl)-ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile,the title compound was prepared as an white crystalline powder (0.012gm, 60%), LC/MS (M+H)⁺: 286, ¹H NMR (DMSO-d₆) δ 12.05 (bs, 1H), 9.32 (s,1H), 8.59 (m, 1H), 8.55 (m, 1H), 8.36 (m, 1H), 8.30 (d, 1H, J=5.2), 7.83(m, 1H), 7.75 (m, 1H), 7.63 (m, 1H), 7.51 (d, 1H, J=5.2), 7.12 (m, 1H).

Example 250:4-{1-[(1R)-1-Methylbutyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine(250a) and4-{1-[(1S)-1-Methylbutyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine(250b)

Step 1.4-[1-(1-Methylbutyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine

4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine(50 mg, 0.0002 mol) (see, Example 231, Step 1) was dissolved in DMF (2mL, 0.02 mol) and cooled at 0° C. This solution was treated with sodiumhydride (7.0 mg, 0.00029 mol) (60% in oil) and stirred for 15 min. Themixture was then treated with 2-bromopentane (40 mg, 0.0002 mol) and wasstirred for 5 h. The reaction was partitioned between ethyl acetate andwater. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated to give the crude product4-[1-(1-methylbutyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridineas an oil, LC/MS (M+H)⁺: 286.

Step 2. 4-[1-(1-Methylbutyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine

Using a procedure analogous to Example 106, Step 4, but using4-[1-(1-methylbutyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine,the title compound was prepared as an white amorphous powder (0.025 gm,60%), LC/MS (M+H)⁺: 255, ¹H NMR (DMSO-d₆) δ 12.21 (bs, 1H), 8.66 (s,1H), 8.27 (bs, 1H), 8.25 (s, 1H), 7.62 (m, 1H), 7.49 (m, 1H), 7.02 (m,1H), 4.46 (m, 1H), 1.9-1.8 (m, 1H), 1.7-1.6 (m, 1H), 1.47 (d, 3H),1.2-1.0 (m, 2H), 0.83 (t, 3H).

Step 3. Separation of Enantiomers

The separation of the enantiomers of4-[1-(1-methylbutyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine fromStep 2 was performed by chiral column preparative HPLC separation usingan OD-H column eluting with an isopropanol:hexane gradient to give thetitle compounds as amorphous white residues, LC/MS (M+H)⁺: 255, ¹H NMR(DMSO-d₆) δ 12.21 (bs, 1H), 8.66 (s, 1H), 8.27 (bs, 1H), 8.25 (s, 1H),7.62 (m, 1H), 7.49 (m, 1H), 7.02 (m, 1H), 4.46 (m, 1H), 1.9-1.8 (m, 1H),1.7-1.6 (m, 1H), 1.47 (d, 3H), 1.2-1.0 (m, 2H), 0.83 (t, 3H).

Example 286:4-Methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile

Step 1.4-Methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile

To a mixture of4-(1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridine(0.050 g, 0.00016 mol) (see, Example 231, Step 1) and cesium carbonate(0.10 g, 0.00032 mol) in dry DMF (1.0 mL, 0.013 mol) was added3-fluoro-4-methylbenzonitrile (0.043 g, 0.00032 mol). The reactionmixture was heated in sealed tube to 120° C. for 5.5 hours. The reactionwas allowed to cool and partitioned between ethyl acetate and water. Theorganic layer was washed with water, brine, dried over magnesiumsulfate, filtered, and concentrated to give4-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrileas a crude product, LC/MS (M+H)⁺: 430.

Step 2.4-Methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile

Using a procedure analogous to Example 106, Step 4, but using4-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile,the title compound was prepared as a white amorphous powder (0.037 gm,88%), LC/MS (M+H)⁺: 300, ¹H NMR (DMSO-d₆) δ 12.19 (bs, 1H), 8.98 (s,1H), 8.57 (s, 1H), 8.31 (d, 1H, J=7.0), 8.08 (s, 1H), 7.89 (d, 1H,J=10), 7.66 (d, 1H, J=10), 7.63 (m, 1H), 7.55 (d, 1H), 7.07 (m, 1H), 2.4(s, 3H).

Further example compounds of the invention are provided in Tables 7, 8,9, 10, and 11 below. The compounds listed in Tables 7, 8, 9, 10 and 11are racemic unless the enantiomers are indicated separately.

TABLE 7

Ex. MS Prepa- No. R (M + H)⁺ Name ration 101

239 2-(1H-pyrrolo[2,3-b]pyridin-4- yl)-4,5,6,7-tetrahydro-2H- indazoleEx 100 102

280 5-nitro-2-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-2H-indazole Ex 100 103

280 6-nitro-2-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-2H-indazole Ex 100 104

286 3-[1-(1H-pyrrolo[2,3-b]pyridin- 4-yl)-1H-imidazol-4-yl]-benzonitrile Ex 100 105

291 4-[4-(3-methoxyphenyl)-1H- imidazol-1-yl]-1H-pyrrolo[2,3- b]pyridineEx 100 106

277 4-(5-phenyl-2-thienyl)-1H- pyrrolo[2,3-b]pyridine Ex 107

TABLE 8

Ex. MS No. —(Y)_(n)—Z (M + H)⁺ Name Preparation 121

279 4-[3-(4-fluorophenyl)-1H-pyrazol-1- yl]-1H-pyrrolo[2,3-b]pyridine Ex120 122

306 4-[3-(3-nitrophenyl)-1H-pyrazol-1- yl]-1H-pyrrolo[2,3-b]pyridine Ex120 123

295 4-[3-(4-chlorophenyl)-1H-pyrazol-1- yl]-1H-pyrrolo[2,3-b]pyridine Ex120 124

291 4-[3-(4-methoxyphenyl)-1H-pyrazol- 1-yl]-1H-pyrrolo[2,3-b]pyridineEx 120 125

286 4-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-3-yl]benzonitrileEx 120 126

276 3-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-3-yl]aniline Ex 120129

291 4-[3-(3-methoxyphenyl)-1H-pyrazol- 1-yl]-1H-pyrrolo[2,3-b]pyridineEx 128 130

316 {3-[1-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-3-yl]-phenoxy}acetonitrile Ex 128 131

343 2-cyano-N-{3-[1-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}acetamide Ex 128 132

405 3-cyano-N-{3-[1-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}acetamide Ex 128

TABLE 9

Mass Ex. Spec No. —(Y)_(n)—Z (M + H)⁺ Name Prep. 150

306 4-[4-(4-nitrophenyl)-1H-pyrazol-1-yl]- 1H-pyrrolo[2,3-b]pyridine Ex153 151

276 4-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-4-yl]aniline Ex 153152

261 4-(4-phenyl-1H-pyrazol-1-yl)-1H- pyrrolo[2,3-b]pyridine Ex 153 154

262 4-(4-pyridin-3-yl-1H-pyrazol-1-yl)-1H- pyrrolo[2,3-b]pyridine Ex 153155

286 2-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-4-yl]benzonitrileEx 153 156

300 {2-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]phenyl}acetonitrile Ex 153 157

306 4-[4-(3-nitrophenyl)-1H-pyrazol-1-yl]- 1H-pyrrolo[2,3-b]pyridine Ex153 158

276 3-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-4-yl]aniline Ex 153159

300 {3-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]phenyl}acetonitrile Ex 153 160

286 4-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-4-yl]benzonitrileEx 153 161

277 3-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-4-yl]phenol Ex 153162

319 methyl 3-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]benzoate Ex 153 163

300 {4-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]phenyl}acetonitrile Ex 153 164

343 2-cyano-N-{3-[1-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-1H-pyrazol-4-yl]-phenyl}acetamide Ex 153 165

277 4-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-4-yl]phenol Ex 153166

287 5-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]nicotinonitrile Ex 153 167

316 {4-[1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]phenoxy}acctonitrile Ex 153 168

265 4-(4-cyclohex-1-en-1-yl-1H-pyrazol-1- yl)-1H-pyrrolo[2,3-b]pyridineEx 172 169

291 4-[4-(4-methoxyphenyl)-1H-pyrazol-1- yl]-1H-pyrrolo[2,3-b]pyridineEx 153 171

263 4-(4-pyrimidin-4-yl-1H-pyrazol-1-yl)- 1H-pyrrolo[2,3-b]pyridine Ex171 174

316 3-{hydroxy[1-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-1H-pyrazol-4-yl]-methyl}benzonitrile Ex 172 175

279 4-[4-(cyclohex-1-en-1-ylmethyl)-1H-pyrazol-1-yl]-1H-pyrrolo[2,3-b]pyridine Ex 172

TABLE 10

Ex. MS No. (M + H)⁺ —(Y)_(n)—Z Name Prep. 202 335

4-[1-(3,5-dimethoxybenzyl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridineEx 201 203 289

4-[1-(1-phenylethyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 201204 281

4-[1-(cyclohexylmethyl)-1H-pyrazol- 4-yl]-1H-pyrrolo[2,3-b]pyridine Ex201 205 300

3-{[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]methyl}benzonitrile Ex 201 206 300

2-{[4-(1H-pyirolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]methyl}benzonitrile Ex 201 207 300

4-{[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]methyl}benzonitrile Ex 201 208 303

1-phenyl-2-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1- yl]ethanoneEx 201 209 283

3,3-dimethyl-1-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-2-one Ex 201 210 280

4-{1-[(5-methylisoxazol-3- yl)methyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 201 211 283

4-[1-(tetrahydro-2H-pyran-2- ylmethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine Ex 201 212 265

4-(1-cyclohex-2-en-1-yl-1H-pyrazol- 4-yl)-1H-pyrrolo[2,3-b]pyridine Ex201 213 255

4-[1-(1-ethylpropyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 201214 267

4-(1-cyclohexyl-1H-pyrazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine Ex 201 215242

2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]acetamide Ex 201216 376

4′-{[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]methyl}biphenyl-2-carbonitrile Ex 201 217 320

4-[1-(2-nitrobenzyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 201218 397, 399

4-{1-[2,6-dichloro-4- (trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 201 220 320

4-[1-(3-nitrobenzyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 201221 353, 355

4-[1-(2-bromobenzyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 201222 332

N-phenyl-2-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]propanamide Ex 201 223 359

4-{1-[3-(trifluoromethoxy)benzyl]- 1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 201 224 361

4-{1-[2-fluoro-5-(trifluoromethyl)- benzyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 201 225 343

4-{1-[3-(trifluoromethyl)benzyl]-1H- pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 201 226 276

4-[1-(pyridin-3-ylmethyl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridineEx 201 227 317

4-{1-[(1S)-1-phenylbutyl]-1H- pyrazol-4-yl}-1H-pyrrolo[2,3- b]pyridineEx 201 228 317

4-{1-[(1R)-1-phenylbutyl]-1H- pyrazol-4-yl}-1H-pyrrolo[2,3- b]pyridineEx 201 229 317

1-phenyl-2-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]propan-1-one Ex 201 230 343, 345

4-[1-(2,6-dichlorobenzyl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridineEx 201 232 289

4-[1-(2,6-dimethylphenyl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridineEx 231 233 354

2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-5-(trifluoromethyl)- benzonitrile Ex 286 234 393, 395

4-[1-(4-bromo-3,5,6-trifluoropyridin- 2-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine Ex 286 235 239

4-[1-(cyclopropylmethyl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridine Ex201 236 289

4-[1-(2,5-dimethylphenyl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridineEx 231 237 275

4-[1-(2-methylphenyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 231238 291

4-[1-(2-methoxyphenyl)-1H-pyrazol- 4-yl]-1H-pyrrolo[2,3-b]pyridine Ex231 239 314

3-{1-[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]ethyl}benzonitrile Ex 250 240 320

3-chloro-4-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile Ex 286 241 295

4-[1-(1-cyclohexylethyl)-1H-pyrazol- 4-yl]-1H-pyrrolo[2,3-b]pyridine Ex250 242 304

4-fluoro-2-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile Ex 286 243 304

2-fluoro-4-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile Ex 286 244 304

3-fluoro-4-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile Ex 286 245 357

4-(1-{1-[3-(trifluoromethyl)- phenyl]ethyl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine Ex 250 246 289

4-[1-(3,5-dimethylphenyl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridineEx 231 247 286

4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]benzonitrile Ex231 248 300

{4-[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]phenyl}acetonitrile Ex 231 249 283

4-[1-(1-methylhexyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 250251 241

4-(1-sec-butyl-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine Ex 250 252303

4-[1-(1-phenylpropyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 250253 367

4-(1-{1-[4-(methylsulfonyl)- phenyl]ethyl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine Ex 250 254 337

4-{1-[1-(3-fluoro-4-methoxy- phenyl)ethyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 250 255 357

4-(1-{1-[2-(trifluoromethyl)- phenyl]ethyl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine Ex 250 256 425

4-(1-{1-[3,5-bis(trifluoromethyl)- phenyl]ethyl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine Ex 250 257 314

4-{1-[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]ethyl}benzonitrile Ex 250 258 374

4-{1-[4-nitro-2- (trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 286 259 300

3-methyl-4-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile Ex 286 260 295, 297

4-[1-(2-chlorophenyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 231261 364, 366

3-bromo-4-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile Ex 286 262 333

ethyl 4-[4-(1H-pyrrolo[2,3-b]pyridin- 4-yl)-1H-pyrazol-1-yl]benzoate Ex286 263 408, 410

4-{1-[2-chloro-6-nitro-4-(trifluoro- methyl)phenyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 286 264 357

4-(1-{1-[4-(trifluoromethyl)- phenyl]ethyl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine Ex 250 265 301

4-[1-(2,3-dihydro-1H-inden-1-yl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine Ex 250 266 315

4-[1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridine Ex 250 267 391

4-(1-{1-[2-chloro-5-(trifluoromethyl)-phenyl]ethyl}-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine Ex 250 268 375

4-{1-[1-(2,4-dichloro-5-fluoro- phenyl)ethyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 250 269 281

4-[1-(1-cyclopentylethyl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3- b]pyridineEx 250 270 317

4-[1-(1-methyl-3-phenylpropyl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine Ex 250 271 267

4-[1-(1-cyclobutylethyl)-1H-pyrazol- 4-yl]-1H-pyrrolo[2,3-b]pyridine Ex250 272 368

[2-[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]-5-(trifluoromethyl)phenyl]acetonitrile Ex 286 273 368

[5-[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]-2-(trifluoromethyl)phenyl]acetonitrile Ex 286 274 253

4-{1-[(3E)-pent-3-en-1-yl]-1H- pyrazol-4-yl}-1H-pyrrolo[2,3- b]pyridineEx 250 275 238

2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex250 276 315

4-{1-[(3E)-4-phenylbut-3-en-1-yl]- 1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 250 277 280

6-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]hexanenitrile Ex250 278 314

ethyl 3-amino-2-{[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]-methyl}propanoate Ex 250 279 285

ethyl 2-[4-(1H-pyrrolo[2,3-b]pyridin- 4-yl)-1H-pyrazol-1-yl]propanoateEx 250 280 283

4-[1-(1-propylbutyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 250281 252

4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]butanenitrile Ex250 282 402, 404

[3-chloro-2-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]-5-(trifluoromethyl)phenyl]acetonitrile Ex 286 283 354

5-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-2-(trifluoromethyl)- benzonitrile Ex 286 284 363, 365

4-{1-[2-chloro-4-(trifluoromethyl)- phenyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 286 285 354

4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-2-(trifluoromethyl)- benzonitrile Ex 286 287 286

2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]benzonitrile Ex286 288 320, 322

3-chloro-2-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile Ex 286 289 362

4-amino-5,6-difluoro-2-[4-(1H- pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]isophthalonitrile Ex 286 290 264

1-{[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]methyl}-cyclopropanecarbonitrile Ex 250 291 280

5-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]hexanenitrile Ex250 292 308

2,2-dimethyl-6-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]-hexanenitrile Ex 250 293 269

4-[1-(1-ethyl-2-methylpropyl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine Ex 250 294 364, 366

5-bromo-2-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile Ex 286 295 354

3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-4-(trifluoromethyl)- benzonitrile Ex 286 296 354

2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-3-(trifluoromethyl)- benzonitrile Ex 286 297 372

3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-4-(trifluoromethyl)- benzamide Ex 286 298 281

3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]cyclohexanone Ex61 299 283

2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]cyclohexanol Ex250 300 360

4-(1-{[1-(methylsulfonyl)piperidin- yl]methyl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine Ex 250 301 292

2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]cyclohexanecarbonitrile Ex 61 302 329

4-{1-[2-(trifluoromethyl)phenyl]-1H- pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine Ex 286 303 329, 331

4-[1-(2,6-dichlorophenyl)-1H- pyrazol- 4-yl]-1H-pyrrolo[2,3-b]pyridineEx 286 304 311

(4-{[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]methyl}-cyclohexyl)methanol Ex 250 305 269

4-[1-(tetrahydrofuran-2-ylmethyl)- 1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine Ex 250 306 295

4-[1-(1-cyclopentylpropyl)-1H- pyrazol- 4-yl]-1H-pyrrolo[2,3-b]pyridineEx 250 307 269

4-[1-(tetrahydrofuran-3-ylmethyl)- 1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine Ex 250 308 320

2-chloro-3-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile Ex 286 309 321

3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-3-(1,3-thiazol-5-yl)- propanenitrile Ex 61 310 372

1-benzyl-4-{[4-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-1H-pyrazol-1-yl]-methyl}pyrrolidin-2-one Ex 250 311 318

3-(1-methyl-1H-imidazol-5-yl)-3-[4- (1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol- 1-yl]propanenitrile Ex 61 312 320

3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]-3-(3-thienyl)propanenitrile Ex 61 313 292

{1-[4-(1H-pyrrolo[2,3-b]pyridin-4- yl)-1H-pyrazol-1-yl]cyclopentyl}acetonitrile Ex 61 314 320, 322

4-chloro-3-[4-(1H-pvrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile Ex 286 315 311

4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]phthalonitrile Ex286 316 303

3-methyl-4-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]benzaldehyde Ex 286 317 320

4-[1-(2-methyl-4-nitrophenyl)-1H- pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine Ex 286 318 267

3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H-pyrazol-1-yl]cyclopentanone Ex201 319 265

4-[1-(3-furylmethyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 201320 265

4-[1-(2-furylmethyl)-1H-pyrazol-4- yl]-1H-pyrrolo[2,3-b]pyridine Ex 201321 339

3-{2-cyano-1-[4-(1H-pyrrolo[2,3-b]-pyridin-4-yl)-1H-pyrazol-1-yl]ethyl}- benzonitrile Ex 61 322 305

{3-methyl-4-[4-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-1H-pyrazol-1-yl]-phenyl}methanol Ex 286 323 283

4-methyl-4-[4-(1H-pyrrolo[2,3- b]pyridin-4-yl)-1H-pyrazol-1-yl]pentan-2-one Ex 61 324 354

3-(1-benzofuran-2-yl)-3-[4-(1H- pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 325 304

3-(3-furyl)-3-[4-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-1H-pyrazol-1-yl]-propanenitrile Ex 61 326 314

{3-methyl-4-[4-(1H-pyrrolo[2,3-b]- pyridin-4-yl)-1H-pyrazol-1-yl]-phenyl}acetonitrile Ex 286

TABLE 11

MS Ex. No. —(Y)_(n)—Z (M + H)⁺ Name Prep. 400

301 4-methyl-3-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-benzonitrile trifluoroacetate Ex 286 401

296 4-[1-(1-cyclopentylpropyl)-1H- pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidine trifluoroacetate Ex 201 402

293 {1-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]cyclo-pentyl}acetonitrile trifluoroacetate Ex 61 403R

340 3-{(1R)-2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}benzonitrile trifluoroacetate Ex 61 403S

340 3-{(1S)-2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}benzonitrile trifluoroacetate Ex 61 404

321 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]-3-(3-thienyl)propanenitrile trifluoroacetate Ex 61 405

321, 323 4-chloro-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]- benzonitrile Ex 286 406

305 3-(3-furyl)-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile Ex 61 407

278 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]-pentanedinitrile Ex 407 408

307 3-{1-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-cyclopentyl}propanenitrile Ex 61 409

307 {1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexyl}- acetonitrile trifluoroacetate Ex 61410

306 {3-methyl-4-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-phenyl}methanol trifluoroacetate Ex 286 411

316 3-pyridin-4-yl-3-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 61 412

316 3-pyridin-3-yl-3-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 413

360 3-[4-(methylthio)phenyl]-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 414

345 3-(3-methoxyphenyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 415

345 3-(4-methoxyphenyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 61 416

314 {3-methyl-4-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-phenyl}acetonitrile trifluoroacetate Ex 153 417

376 3-[4-(methylsulfinyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 61418

392 3-[4-(methylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 61419

369 3-[3-(cyanomethoxy)phenyl]-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 61 420

349 351 3-(6-chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- pyrazol-1-yl]propanenitrile Ex 61 421

340 5-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyridine-2-carbonitrile trifluoroacetate Ex 421 422

334 3-(3,5-dimethylisoxazol-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitriletrifluoroacetate Ex 61 423

384 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]- propanenitrile trifluoroacetate Ex 61424

345 3-(6-methoxypyridin-3-yl)-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 425

316 3-pyridin-2-yl-3-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 61 426

394 396 3-(6-bromopyridin-2-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- pyrazol-1-yl]propanenitriletrifluoroacetate Ex 61 427

341 6-{2-cyano-1-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-ethyl}pyridine-2-carbonitrile trifluoroacetate Ex 421 428

306 4-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]-heptanedinitrile Ex 428 429

393 395 3-(5-bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- pyrazol-1-yl]propanenitrile Ex 429 430

288 4-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]-heptanedinitrile Ex 430 431

340 5-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}nicotinonitrile trifluoroacetate Ex 431 432

345 3-(2-methoxypyridin-3-yl)-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 433

369 3-[4-(cyanomethoxy)phenyl]-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 434

369 3-[2-(cyanomethoxy)phenyl]-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 435

473 3-(3,5-dibromophenyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 61 436

365 5-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}isophthalonitrile trifluoroacetate Ex 431 437

359 3-[6-(dimethylamino)pyridin-2-yl]- 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propane- nitrile trifluoroacetate Ex 421 438

401 399 3-(4-bromo-2-thienyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- pyrazol-1-yl]propanenitriletrifluoroacetate Ex 61 439

346 5-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}thiophene-3-carbonitrile trifluoroacetate Ex 431 440

410 412 3-(5-bromo-2-fluorophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitriletrifluoroacetate Ex 61 441

359 3-(3-nitrophenyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 442

422 424 3-(5-bromo-2-methoxyphenyl)-3- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 61 443

369 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-4-methoxybenzonitrile trifluoroacetate Ex 61 444

392 394 3-(3-bromophenyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 445

357 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-4-fluorobenzonitrile trifluoroacetate Ex 61 446

447 449 3-[5-bromo-2-(cyanomethoxy)- phenyl]-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile Ex 61 447

385 383 3-(4-bromo-2-furyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 61 448

394 4-(cyanomethoxy)-3-{2-cyano-1- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}- benzonitrile trifluoroacetate Ex 61 449

396 394 3-(4-bromopyridin-2-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- pyrazol-1-yl]propanenitrile Ex 61 450

341 2-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}isonicotinonitrile trifluoroacetate Ex 431 451

330 5-{2-cyano-1-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-ethyl}-3-furonitrile trifluoroacetate Ex 431 452

447 449 3-[2-bromo-5-(cyanomethoxy)- phenyl]-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile Ex 61 453

394 4-(cyanomethoxy)-2-{2-cyano-1- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}- benzonitrile trifluoroacetate Ex 61 454

317 3-pyrimidin-5-yl-3-[4-(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol- 1-yl]propanenitrile trifluoroacetateEx 61 455

396 394 3-(2-bromopyridin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- pyrazol-1-yl]propanenitriletrifluoroacetate Ex 61 456

341 4-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyridine-2-carbonitrile trifluoroacetate Ex 421 457

346 3-(5-methoxypyridin-3-yl)-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 458

348 3-(3-chlorophenyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 459

382 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]-3-[3-(trifluoromethyl)phenyl]- propanenitrile trifluoroacetate Ex 61 460

406 3-(3-phenoxyphenyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 461

398 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]-3-[3-(trifluoromethoxy)phenyl]propane- nitrile trifluoroacetate Ex 61 462

373 methyl 3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}benzoate Ex 61 463

359 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}benzoic acid Ex 61 464

380 3-[3-(1H-pyrazol-4-yl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 482467

329 3-(3-aminophenyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Bis trifluoroacetate Ex 467 468

371 N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)- acetamide trifluoroacetate Ex 468 469

407 N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)- methanesulfonamide Ex 468 470

346 4-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}thiophene-2-carbonitrile trifluoroacetate Ex 470 471

346 5-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}thiophene-2-carbonitrile trifluoroacetate Ex 471 472

428 3-[3-(morpholin-4-ylcarbonyl)- phenyl]-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile trifluoroacetate Ex 472475

401 N-(2-aminoethyl)-3-{2-cyano-1-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}benzamide Bis trifluoroacetate Ex 472 476

349 3-(5-formyl-3-thienyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile trifluoroacetate Ex 61 477

372 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-methylbenzamide trifluoroacetate Ex 472 478

396 2-cyano-N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)- acetamide trifluoroacetate Ex 472 479

434 N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)- nicotinamide Bis trifluoroacetate Ex 478 480

414 N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)-N′- isopropylurea trifluoroacetate Ex 468 481

415 isopropyl (3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)- carbamate trifluoroacetate Ex 468 482

392 3-(5-phenylpyridin-3-yl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile- trifluoroacetate Ex 482 483

393 3-(3,3′-bipyridin-5-yl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile- trifluoroacetate Ex 482 484

394 3-(5-pyrimidin-5-ylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-1H-pyrazol-1-yl]propanenitrile Ex482 485

396 3-[5-(1-methyl-1H-pyrazol-4-yl)- pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile trifluoroacetate Ex482 486

339 3-(5-ethynylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H- pyrazol-1-yl]propanenitriletrifluoroacetate Ex 486 488

424 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitriletrifluoroacetate Ex 488 489

402 400 3-(2-bromo-1,3-thiazol-5-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 61490

300 ethyl 3-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-butanoate Ex 61 491

401 3-(5-morpholin-4-ylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-1H-pyrazol-1-yl]propanenitrile Ex491 492

319 3-(1-methyl-1H-pyrazol-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 61493

357 4-{1-[1-phenyl-2-(1H-1,2,4-triazol- 1-yl)ethyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidine Ex 250 494

357 4-{1-[1-phenyl-2-(4H-1,2,4-triazol- 4-yl)ethyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidine Ex 250 495

392 3-(3-pyridin-3-ylphenyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 482 496

440 3-[5-(phenylsulfinyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]propane- nitriletrifluoroacetate Ex 496 497

456 3-[5-(phenylsulfonyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]propane- nitriletrifluoroacetate Ex 497 498

272 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]pentan-1-olEx 498 499

330 methyl 3-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentyl carbonate Ex 499 500(a)

285 (1E)-3-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanal oxime Ex 500 501

299 (1E)-3-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanal O-methyloxime Ex 501 502

299 (1Z)-3-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanal O-methyloxime Ex 502 503

426 4-[1-(4,4-dibromo-1-ethylbut-3-en- 1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate Ex 503 504

431 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]-3-[5-(1,3-thiazol-2-ylthio)pyridin-3-yl]- propanenitrile bis(trifluoroacetate) Ex488 505

376 3-[5-(ethylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 488506

266 4-[1-(1-ethylbut-3-yn-1-yl)-1H- pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate Ex 506 507

295 4-{1-[1-methyl-2-(1H-1,2,4-triazol- 1-yl)ethyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidine Ex 250 508

270 4-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]pentan-2-onetrifluoroacetate Ex 61 509

318 1-phenyl-2-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-one Ex 250 510

392 3-[5-(ethylsulfinyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-1H-pyrazol-1-yl]propanenitrile Ex496 511

408 3-[5-(ethylsulfonyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-1H-pyrazol-1-yl]propanenitrile Ex497 512

430 3-[5-(cyclohexylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]- propanenitrileEx 488 513 de#1

320 1-phenyl-2-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol Ex 509 513 de#2

320 1-phenyl-2-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-propan-1-ol Ex 509 514

375 3-[3-(ethylthio)phenyl]-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 516 515

391 3-[3-(ethylsulfinyl)phenyl]-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 516 516 ee#1

407 3-[3-(ethylsulfonyl)phenyl]-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 516 516 ee#2

407 3-[3-(ethylsulfonyl)phenyl]-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 516 517

462 3-[5-(cyclohexylsulfonyl)pyridin-3- yl]-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile Ex 497 518

446 3-[5-(cyclohexylsulfinyl)pyridin-3- yl]-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile Ex 496 519

304 4-[1-(1-methyl-2-phenylethyl)-1H- pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidine Ex 250 520

310 4-{1-[1-methyl-2-(3-thienyl)ethyl]- 1H-pyrazol-4-yl}-7H-pyrrolo-[2,3-d]pyrimidine Ex 250 521

315 3-{1-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-ethyl}benzonitrile Ex 250 522

294 4-{1-[2-(1H-imidazol-1-yl)-1- methylethyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidine Ex 250 523

310 4-{1-[1-methyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-1H-pyrazol-4- yl}-7H-pyrrolo[2,3-d]pyrimidine Ex250 524

393 3-[3-(methylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 516525

392 3-(3-pyridin-4-ylphenyl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile Ex 482 526

268 4-[1-(1-ethylbut-3-en-1-yl)-1H- pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidine Ex 526 527

268 4-[1-(1,3-dimethylbut-3-en-1-yl)- 1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine Ex 526 528

390 3-[5-(isopropylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-1H-pyrazol-1-yl]propanenitrile Ex488 529

406 3-[5-(isopropylsulfinyl)pyridin-3- yl]-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile Ex 496 530

422 3-[5-(isopropylsulfonyl)pyridin-3- yl]-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile Ex 497 531 ee#1

384 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]-3-[5-(trifluoromethyl)pyridin-3-yl]- propanenitrile Ex 431 531 ee#2

384 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]-3-[5-(trifluoromethyl)pyridin-3-yl]- propanenitrile Ex 431 532

401 2-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]-N-[3-(trifluoromethyl)phenyl]- propanamide Ex 250 533

383 N-2-naphthyl-2-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanamide Ex 250 534

383 N-1-naphthyl-2-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanamide Ex 250 535

358 N-(3-cyanophenyl)-2-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanamide Ex 250 536

347 N-benzyl-2-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanamide Ex 250 537

347 N-phenyl-2-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-butanamide Ex 250 538

439 N-(4-phenoxyphenyl)-2-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanamide Ex 250 539

397 N-2-naphthyl-2-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanamide Ex 250 540

372 N-(3-cyanophenyl)-2-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanamide Ex 250 541

423 N-biphenyl-4-yl-2-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanamide Ex 250 542

437 N-(biphenyl-4-ylmethyl)-2-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanamide Ex 250 543

437 N-(biphenyl-3-ylmethyl)-2-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanamide Ex 250 544

372 N-(4-cyanophenyl)-2-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanamide Ex 250 545

397 N-1-naphthyl-2-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanamide Ex 250 546

435 5-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-phenylnicotinamide trifluoroacetate Ex 431 547

430, 432 4-{1-[1-(5-bromopyridin-3-yl)-4,4-difluorobut-3-en-1-yl]-1H-pyrazol- 4-yl}-7H-pyrrolo[2,3-d]pyrimidine Ex717 548

378 5-{4,4-difluoro-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-en-1- yl}nicotinonitrile Ex 717

Example 407:3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedinitrile

Step 1: Dimethyl3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate

4-(1H-Pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(31.0 g, 0.0983 mol) was suspended in ACN (620 mL, 12 mol), and DBU (9.3mL, 0.062 mol) was added under nitrogen. The reaction was heated to 65°C. and dimethyl (2E)-pent-2-enedioate (16 mL, 0.12 mol) was added in 5mL portions over 2 h. After stirring overnight, the reaction wascomplete. The reaction was allowed to cool to room temperature and wasconcentrated in vacuo to give a dark oil. The oil was partitionedbetween ethyl acetate and water. The organic layer was washed with 1.0 NHCl, brine, dried over magnesium sulfate, and then concentrated to givea dark oil. The viscous oil was triturated with ethyl ether 3×500 mL togive a dark precipitate. The oil was taken up in ethyl acetate to form asolid. The solids were collected, washed with ethyl ether and dried togive dimethyl3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioateas a white powder (29.5 gm, 64%), LC/MS (M+H)⁺: 474, ¹H NMR (DMSO-d₆) δ9.1 (s, 1H), 9.02 (s, 1H), 8.65 (s, 1H), 8.11 (d, 1H), 7.42 (d, 1H),5.78 (s, 2H), 5.27 (m, 1H), 3.65 (m, 8H), 3.15 (m, 4H), 0.95 (t, 2H),0.1 (s, 9H).

Step 2:3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]-pentanedioicacid

Dimethyl3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate(43.0 g, 0.0908 mol) was dissolved in methanol (271.2 mL, 6.695 mol) andlithium hydroxide monohydrate (15 g, 0.36 mol) dissolved in water (125mL) was added. The reaction was stirred at rt for 2 h. The methanol wasremoved in vacuo and a resulting aqueous layer was cooled in an icebath. The solution was made acidic pH-4 with 1N HCl to give a whiteprecipitate. The solid precipitate was collected, washed with water,dried to give3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioicacid as a white crystalline powder (31.8 gm, 80%), LC/MS (M+H)⁺: 446, ¹HNMR (DMSO-d₆) δ 8.85□s□□1H), 8.75 (s, 1H), 8.42 (s, 1H), 7.85 (d, 1H),7.17 (d, 1H), 5.71 (s, 2H), 5.18 (m, 1H), 3.65 (t, 2H), 3.05 (m, 4H),0.92 (t, 2H), 0.1 (s, 9H).

Step 3:3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanediamide

3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioicacid (31.80 g, 0.07137 mol) was dissolved in DMF (636 mL, 8.21 mol)under nitrogen cooled in an ice bath and CDI (34.7 g, 0.214 mol) wasadded. This mixture was allowed to stir for 30 minutes and then allowedto warm to rt. After stirring for 2 h ammonia (12.2 g, 0.714 mol) wasbubbled through the solution for 30 minutes giving a cloudy suspension.The reaction mixture was concentrated to remove some of the DMF (˜200mL) and then water was added slowly to give a white precipitate. Thismixture was cooled in an ice bath and the solid precipitate wascollected, washed with water and dried in vacuo to give3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanediamideas a white powder (29.0 gm, 91%), LC/MS (M+H)⁺: 444, ¹H NMR (DMSO-d₆) δ8.85 (s, 1H), 8.59 (s, 1H), 8.40 (s, 1H), 7.87 (d, 1H), 7.75 (s, 2H),7.15 (d, 1H), 6.95 (s, 2H), 5.73 (s, 2H), 5.29 (m, 1H), 3.63 (t, 2H),2.82 (m, 2H), 2.73 (m, 2H), 0.90 (t, 2H), 0.1 (s, 9H).

Step 4:3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentanedinitrile

3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanediamide(29.0 g, 0.0654 mol) was partially dissolved in DMF (200 mL, 2 mol), DCM(200 mL, 3 mol) and TEA (36 mL, 0.26 mol) and cooled in an ice bathunder nitrogen atmosphere. The trichloroacetyl chloride (15 mL, 0.14mol) was added dropwise turning the reaction to a dark solution. Thiswas stirred at 0° C. for ½ h. The reaction was then concentrated toremove the DCM and the resulting DMF solution was diluted with water toprecipitate the product. The solid precipitate was collected and washedwith water to give a dark solid. The solid was then dissolved in DCM andwashed with brine, dried over magnesium sulfate and concentrated to givea very dark oily residue. The residue was taken up in DCM, and hexanewas added until the solution became slightly cloudy. This was stirred atrt to precipitate3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedinitrileas white needle-like crystals (22.7 gm, 85%), LC/MS (M+H)⁺: 408, ¹H NMR(DMSO-d₆) δ 9.07 (s, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 7.88 (d, 1H), 7.19(d, 1H), 5.75 (s, 2H), 5.30 (m, 1H), 3.62 (t, 2H), 3.40 (m, 4H), 0.91(t, 2H), 0.10 (s, 9H).

Step 5:3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedinitrile

3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedinitrile(10.0 g, 0.0245 mol) was dissolved in ACN (200 mL, 3.83 mol) and water(20 g, 1.1 mol) at rt. To this lithium tetrafluoroborate (23.0 g, 0.245mol) was added giving a cloudy solution. The reaction was heated toreflux and monitored by HPLC. After heating for 24 h the reaction wasallowed to cool to rt and then cooled in an ice bath. To this, ammoniumhydroxide (23 mL, 0.59 mol) was added slowly. The reaction was allowedto warm to rt. After stirring for 18 hs the reaction was diluted withwater and concentrated in vacuo to remove the ACN, giving a precipitate.The solids were collected, washed with water and dried to give the titlecompound as an off-white solid (6. 2 gm, 91%), LC/MS (M+H)⁺: 278, ¹H NMR(DMSO-d₆) δ 8.9 (s, 1H), 8.72 (s, 1H), 8.43 (s, 1H), 7.59 (d, 1H), 6.92(d, 1H), 5.21 (m, 1H), 3.25 (m, 4H).

Example 421:5-{2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-pyridine-2-carbonitriletrifluoroacetate

Step 1:3-(6-Chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

3-(6-Chloropyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(prepared by methods analogous to those described for Example 61) (0.070g, 0.00014 mol) in TFA (3.0 mL, 0.039 mol) and DCM (3.0 mL, 0.047 mol)was stirred at room temperature for 1 hour. Solvent was removed invacuo, and the residue was dissolved in methanol (4.0 mL, 0.099 mol) andethylenediamine (0.07 mL, 0.001 mol). The reaction mixture was stirredat room temperature overnight. Solvent was removed in vacuo, the crudeproduct was purified by preparative HPLC eluting with an ACN; watergradient buffered with ammonium hydroxide to pH=10, to give3-(6-chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrileas a white powder (35 mg, 69%), LCMS (M+1)⁺:350, ¹H NMR (DMSO-d₆)□ δ12.21 (b, 1H), 9.00 (s, 1H), 8.78 (s, 1H), 8.62 (s, 1H), 8.58 (s, 1H),8.00 (m, 1H), 7.70 (m, 2H), 7.00 (s, 1H), 6.22 (m, 1H), 3.90 (m, 1H),3.78 (m, 1H)

Step 2:5-2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-yl]ethylpyridine-2-carbonitriletrifluoroacetate

A mixture of3-(6-chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(0.025 g, 0.000071 mol) and zinc cyanide (0.08 g, 0.0007 mol) in DMF(1.0 mL, 0.013 mol) was degassed with nitrogen. To this mixture,tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.00004 mol) was addedand the resulting mixture degassed again with dinitrogen. The reactionmixture was heated in a sealed tube at 170° C. for 15 minutes in amicrowave (Personal Chemistry). After cooling to room temperature, thesolids were filtered, rinsed with DMF and the combined solvent wasconcentrated in vacuo. The residue was triturated with hexanes (3×), andhexanes washes were discarded. The crude product was purified bypreparative HPLC eluting with an ACN; water gradient containing 0.2% TFAto give the title compound as a white powder (16 mg, 49.27%), LCMS(M+1)⁺: 341, 1H NMR (DMSO-d₆) δ 12.50 (b, 1H), 9.05 (s, 1H), 8.89 (s,1H), 8.80 (s, 1H), 8.58 (s, 1H), 8.18 (m, 2H), 7.78 (s, 1H), 7.05 (s,1H), 6.20 (m, 1H), 3.90 (m, 1H), 3.77 (m, 1H).

Example 428:4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanedinitrile

Step 1:3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diol

Diethyl3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate,prepared substantially as described in Example 407 (0.80 g, 0.0016 mol),was dissolved in THF (40 mL, 0.49 mol) and cooled in an ice bath under anitrogen atmosphere. To this mixture, 1.0 M lithium tetrahydroaluminatein THF (3.2 mL) was added slowly. The reaction was stirred for 1 h,quenched with ice and partitioned between ethyl acetate and 1 N HCl. Theorganic layer was washed with brine, dried over magnesium sulfate andconcentrated to give an amber oil. The product was purified by FCC onsilica gel eluting with an ethyl acetate: methanol gradient to give3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diolas a clear viscous oil (0.51 gm, 76%), LC/MS (M+H)⁺: 418, ¹H NMR(DMSO-d₆) δ, 8.85 (s, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 7.45 (d, 1H),6.83 (d, 1H), 5.73 (s, 2H), 4.91 (m, 1H), 3.75 (m, 2H), 3.59 (m, 2H),3.45 (m, 2H), 2.18 (m, 4H), 0.95 (m, 2H), 0.1 (s, 9H).

Step 2:3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diyldimethanesulfonate

A mixture of3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diol(50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) was cooled at 0° C. To thismixture, TEA (50 μL, 0.0004 mol) was added. The reaction was stirred for15 minutes. Methanesulfonyl chloride (23 μL, 0.00030 mol) was added andthe resulting mixture was stirred for 1 hour. Water was added and theproduct was extracted with ethyl acetate. The combined extracts werewashed with saturated sodium chloride, dried over magnesium sulfate,filtered and concentrated to give3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentane-1,5-diyldimethanesulfonate (57 mg, 80%) as an oil. MS(ES): 574 (M+1).

Step 3:4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanedinitrile

To a mixture of3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diyldimethanesulfonate (57 mg, 0.000099 mol) in DMSO (1 mL, 0.01 mol),sodium cyanide (10 mg, 0.0003 mol) was added and the mixture was stirredfor 2 hours. The mixture was heated at 60° C. for 1 hour. Water wasadded and the product was extracted with ethyl acetate. The combinedextracts were washed with saturated sodium chloride, dried overmagnesium sulfate, filtered and concentrated to give4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanedinitrile(40 mg, 90%) as an oil. MS(ES): 436 (M+1).

Step 4:4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanedinitrile

Using a procedure analogous to Example 61 for the removal of the SEMprotecting group, the title compound was prepared as a white amorphoussolid, (17 mg, 60%)¹H NMR (400 MHz, DMSO): δ □8.75 (s, 1H), 8.65 (s,1H), 8.4 (s, 1H), 7.6 (d, 1H), 7.0 (d, 1H), 4.5 (m, 1H), 2.35 (m, 4H),2.2 (m, 4H). MS(ES): 306 (M+1).

Example 429:3-(5-Bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

Step 1: (2Z&E)-3-(5-Bromopyridin-3-yl)acrylonitrile

To a mixture of 1.0 M potassium tert-butoxide in THF (2.7 mL) at 0° C.(water-ice bath, under an atmosphere of nitrogen) was added diethylcyanomethylphosphonate (0.48 mL, 0.0030 mol) in THF (4.0 mL, 0.049 mol),dropwise. The reaction mixture was warmed to room temperature, and thenwas cooled to 0° C., followed by dropwise addition of5-bromonicotinaldehyde (0.5 g, 0.003 mol) in THF (1.0 mL, 0.012 mol).After stirring at room temperature for 20 hours, the reaction mixturewas quenched with water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate,filtered, and concentrated to give a crude product as a dark oil. Thecrude product was purified by flash chromatography on silica gel usingethyl acetate-hexanes 3:7 as eluent to give a mixture of cis and transisomers (2)-3-(5-bromopyridin-3-yl)acrylonitrile as an off-white solid(268 mg, 47.69%). LCMS (M+1)⁺: 209, 211, ¹H NMR (400 MHz, CDCl₃): δ□8.75 (s, 1H), 8.62 (s, 1H), 7.90 (s, 1H), 7.40 (d, 1H), 6.00 (d, 1H).

Step 2:3-(5-Bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]propanenitrile

To4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(0.200 g, 0.000634 mol) in 1.0 mL of dry ACN was added DBU (0.10 mL,0.00067 mol), followed by the addition of(2Z&E)-3-(5-bromopyridin-3-yl)acrylonitrile (0.234 g, 0.00112 mol) in1.0 mL of ACN. The reaction mixture was stirred at 67° C. for 4 hours.Upon cooling, the mixture was partitioned between dilute hydrochloricacid and ethyl acetate. The organic layer was washed with saturatedsodium chloride, dried over anhydrous sodium sulfate, and concentrated.The crude product was purified by flash chromatography on silica gelusing ethyl acetate:hexanes (7:3) to give3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)-ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrileas an off-white solid (225 mg, 67.66%). LCMS (M+1)⁺:524, 526: ¹H NMR(400 MHz, CDCl3): δ□ 8.90 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 8.42 (s,1H), 8.40 (s, 1H), 8.00 (s, 1H), 7.50 (d, 1H), 6.82 (d, 1H), 5.81 (m,1H), 5.75 (s, 2H), 3.70 (m, 1H), 3.60 (m, 2H), 3.42 (m, 1H), 1.00 (m,2H), 0.08 (s, 9H).

Step 3:3-(5-Bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

The3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(0.220 g, 0.000419 mol) in DCM (9.0 mL, 0.14 mol) and TFA (9.0 mL, 0.12mol) was stirred at room temperature for 1 hour. The reaction wasconcentrated in to give a residue. This crude intermediate was dissolvedin methanol (12 mL, 0.30 mol) and ethylenediamine (0.2 mL, 0.003 mol)and was stirred overnight at room temperature. The reaction wasconcentrated in vacuo to give the crude product which was purified bypreparative HPLC eluting with a water:ACN gradient buffered withammonium hydroxide (pH=10) to give3-(5-bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrileas an amorphous white powder (118 mg, 71.36%). LCMS (M+1)⁺:394, 396, ¹HNMR (400 MHz, DMSO-d6): δ □12.05 (bs, 1H), 8.98 (s, 1H), 7.0 (s, 1H),6.50 (m, 2H), 8.50 (s, 1H), 8.10 (s, 1H), 7.80 (s, 1H), 6.98 (s, 1H),6.21 (m, 1H), 3.90 (m, 1H), 3.70 (m, 1H).

Example 430:3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diol

Using a procedure analogous to Example 61 for the removal of the SEMprotecting group but using3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentane-1,5-diolfrom Example 428, the title compound was prepared as a white amorphoussolid, (25 mg, 70%)¹H NMR (400 MHz, DMSO): δ □8.65 (s, 1H), 8.6 (s, 1H),8.25 (s, 1H), 7.6 (d, 1H), 6.0 (d, 1H), 4.6 (m, 1H), 3.3 (m, 2H), 3.2(m, 2H), 2.1 (m, 2H), 1.9 (m, 2H). MS(ES): 288 (M+1).

Example 431:5-(2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)-nicotinonitrilebis(trifluoroacetate)

A slurry of3-(5-bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(0.050 g, 0.00013 mol) (from Example 429), DMF (2.0 mL, 0.026 mol) andzinc cyanide (0.1 g, 0.001 mol) was degassed by purging with nitrogen.Then tetrakis(triphenyl-phosphine)palladium(0) (0.07 g, 0.00006 mol) wasadded and the resulting slurry again was degassed with nitrogen. Thereaction was sealed and heated at 170° C. for 15 minutes in a microwave(Personal Chemistry). The reaction was allowed to cool and the solidswere filtered off. The combined DMF fractions were concentrated invacuo. The residue was triturated with ethyl acetate-hexanes 2:8, thenwith ethyl ether to removed by-products. The crude product was purifiedby preparative HPLC eluting with a water:acetontrile gradient containing0.2% TFA to give the racemic title compound (43 mg, 59.65%). LCMS(M+1)⁺:341, ¹H NMR (400 MHz, DMSO-d₆): δ □12.60 (bs, 1H), 9.10 (s, 1H),8.90 (s, 1H), 8.80 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 7.78 (s, 1H),7.10 (s, 1H), 6.30 (m, 1H), 3.90 (m, 1H), 3.70 (m, 1H).

Example 431R and Example 431S

The enantiomersR-5-(2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-ethyl)nicotinonitrileandS-5-(2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-ethyl)nicotinonitrilewere separated by chiral column HPLC.

Example 467:3-(3-Aminophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrilebis(trifluoroacetate)

Step 1:3-(3-Nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

To4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(0.500 g, 0.00158 mol) in 8.0 mL of dry ACN was added DBU (0.24 mL,0.0016 mol) followed by addition of (2Z)-3-(3-nitrophenyl)acrylonitrile(0.36 g, 0.0021 mol) in 2.0 mL of ACN. The reaction mixture was heatedat 67° C. for 18 hours. This was cooled to room temperature, and themixture was partitioned between diluted hydrochloric acid and ethylacetate. The organic layer was washed with saturated sodium chloride,dried over anhydrous magnesium sulfate, and concentrated. The crudeproduct was purified by flash chromatography on silica gel using ethylacetate-hexanes 6:4, to give3-(3-nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrileas a dark orange oil, (688 mg, 88.65%). LCMS (M+1):490

Step 2.3-(3-Aminophenyl)-3-(4-7-[2-(trimethylsilyl)ethoxy]-7H-pyrrolo[2,3-d]pyrimidin-4-yl-1H-pyrazol-1-yl)propanenitrile

The3-(3-nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(0.630 g, 0.00129 mol) was dissolved in ethanol (65 mL, 1.1 mol),degassed with nitrogen, and then palladium (0.55 g, 0.0052 mol) (10% oncarbon) was added. The reaction mixture was again purged with nitrogen,and it was then charged at 50 psi hydrogen in a Parr shaker for 60minutes. The reaction mixture was filtered and concentrated to give3-(3-aminophenyl)-3-(4-7-[2-(trimethylsilyl)ethoxy]-7H-pyrrolo[2,3-d]pyrimidin-4-yl-1H-pyrazol-1-yl)propanenitrileas a colorless oil (550 mg, 95.92%), LCMS (M+1)+=460,

Step 3.3-(3-Aminophenyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrilebis(trifluoroacetate)

Using a procedure analogous to that of Example 61 for the removal of theSEM protecting group, the title compound was prepared as a whiteamorphous solid (18 mg, 38%), LCMS (M+1)+=329: ¹H NMR (DMSO-d₆) δ 12.61(b, 1H), 9.00 (s, 1H), 8.80 (s, 1H), 8.50 (s, 1H), 7.78 (m, 1H), 7.25(m, 1H), 7.18 (m, 1H), 6.85 (m, 2H), 6.02 (m, 1H), 3.78 (m, 1H), 3.60(m, 1H).

Example 468:N-(3-(2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)-phenyl)acetamidetrifluoroacetate

Step 1-(3-2-Cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylphenyl)acetamide

To3-(3-aminophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(0.070 g, 0.00015 mol) (from Example 467) in dry DCM (1.0 mL, 0.016 mol)was added TEA (0.042 mL, 0.00030 mol). The reaction was cooled in an icebath and acetyl chloride (0.016 mL, 0.00023 mol) was added. The reactionmixture stirred for 30 minutes and was diluted with water and extractedwith ethyl acetate (2×). The combined organic layers were washed withsaturated sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo to giveN-(3-2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylphenyl)acetamideas a colorless oil, (65 mg, 85.08%), LCMS(M+1)⁺=502.

Step 2N-(3-2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylphenyl)acetamidetrifluoroacetate

Using a procedure analogous to that of Example 61 for the removal of theSEM protecting group, the title compound was prepared as a whiteamorphous solid (40 mg, 68.9%), LCMS(M+1)+=372, ¹H NMR (DMSO-d₆) δ 12.61(b, 1H), 9.05 (s, 1H), 8.79 (s, 1H), 8.44 (s, 1H), 7.85 (s, 1H), 7.55(s, 1H), 7.48 (d, 1H), 7.24 (m, 1H), 7.10 (m, 2H)), 6.05 (m, 1H), 3.70(m, 1H), 3.48 (m, 1H), 1.98 (s, 3H).

Example 470:4-(2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)-thiophene-2-carbonitriletrifluoroacetate

Step 1 4-Bromo-2-(diethoxymethyl)thiophene

A mixture of 4-bromothiophene-2-carbaldehyde (1.2 g, 0.0063 mol) inethanol (10 mL, 0.2 mol) was treated with ammonium chloride (0.42 g,0.0078 mol) and ethyl orthoformate (1.2 g, 0.0078 mol). The mixture wasstirred at 60° C. for 2 hours. The reaction was quenched with water andextracted with ethyl acetate. The combined organic layer was washed withsaturated sodium chloride, dried over magnesium sulfate, filtered andconcentrated to give 4-bromo-2-(diethoxymethyl)thiophene as an oil (1.3g, 81%). ¹H NMR (400 MHz, CDCl₃): δ□ 7.22 (s, 1H), 6.99 (s, 1H), 5.68(s, 1H), 3.63 (q, 4H) 1.24 (t, 6H).

Step 2 5-(Diethoxymethyl)thiophene-3-carbaldehyde

A solution of 4-bromo-2-(diethoxymethyl)thiophene (500 mg, 0.002 mol) inether (5 mL, 0.05 mol) was cooled at −78° C. To this solution, 2.5 Mn-butyllithium in hexane (0.83 mL) was added dropwise. The reaction wasstirred at −78° C. for 1 hour. To the reaction was added DMF (0.4 g,0.006 mol) at −78° C. and the mixture was stirred for 30 minutes. Thereaction was quenched with water and extracted with ethyl acetate. Thecombined organic layers were washed with saturated sodium chloride,dried over magnesium sulfate, filtered and concentrated. The cruderesidue was purified by flash column chromatography to yield the5-(diethoxymethyl)thiophene-3-carbaldehyde as an oil (170 mg, 42.0%). By¹H NMR two different regioisomers of aldehydes were formed and were notseparated; (note: NMR shifts are for the major isomer only)¹H NMR (400MHz, CDCl₃): δ □9.85 (s, 1H), 8.05, 7.7 (s, 1H), 7.45, 7.15 (s, 1H), 5.7(s, 1H), 3.65 (m, 2H), 1.25 (m, 2H).

Step 3 (2E)-3-[5-(Diethoxymethyl)-3-thienyl]acrylonitrile

To a solution of diethyl cyanomethylphosphonate (100 mg, 0.0008 mol) inTHF (2 mL, 0.02 mol) cooled at 0° C. and 1.0 M potassium tert-butoxidein THF (0.8 mL) was added dropwise. The bath was removed and thereaction was warmed to room temperature for 30 minutes. The reaction wascooled to 0° C. and a solution of5-(diethoxymethyl)thiophene-3-carbaldehyde (170 mg, 0.00079 mol) in THF(2 mL, 0.02 mol) was added drop wise. The reaction was stirred overnightat room temperature. The reaction was partitioned between water andethyl acetate. The combined extracts were washed with saturated sodiumchloride, dried over magnesium sulfate, filtered and concentrated. Thecrude residue was purified by flash column chromatography on silica geleluting (ethyl acetate:hexane, 1:5) to give(2E)-3-[5-(diethoxymethyl)-3-thienyl]acrylonitrile as an oil (160 mg,84.9%). ¹H NMR (300 MHz, CDCl₃): δ □7.4-7.0 (m, 3H), 5.65 (m 1H), 4.2(m, 1H), 3.65 (m, 4H), 1.25 (m, 6H).

Step 4 3-[5-(Diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]propanenitrile

To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(200 mg, 0.0007 mol) in ACN (2 mL, 0.04 mol) and(2E)-3-[5-(diethoxymethyl)-3-thienyl]acrylonitrile (160 mg, 0.00067 mol)(mixture of regioisomers) DBU (80 μL, 0.0005 mol) was added. Thereaction was stirred overnight than water was added and the product wasextracted with ethyl acetate. The combined extracts were washed withsaturated sodium chloride, dried over magnesium sulfate, filtered andconcentrated. The crude residue was purified by flash columnchromatography on silica gel eluting (50% EtOAc/Hexane) to give3-[5-(diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(160 mg, 43%). ¹H NMR (400 MHz, CDCl₃): δ □8.92 (s, 1H), 8.41 (s, 1H),8.29 (b, 1H), 7.45 (d, 1H), 7.41 (d, 1H), 7.15 (s, 1H), 7.05 (d, 1H),6.82 (m, 1H), 5.74 (d, 2H), 3.74 (m, 2H), 3.71 (m, 8H), 3.59 (m, 1H),1.32 (m, 4H), 0.95 (m, 2H), −0.08 (s, 9H); MS(ES):553 (M+1).

Step 53-(5-Formyl-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

A solution of3-[5-(diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(70 mg, 0.0001 mol) in THF (1 mL, 0.01 mol) was treated with 1 M HCl inwater (400 μL). The reaction was stirred at room temperature. Water wasadded and the product was extracted with ethyl acetate. The combinedextracts were washed with saturated sodium chloride, dried overmagnesium sulfate, filtered and concentrated to give3-(5-formyl-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrileas a semisolid residue (60 mg, 98%). ¹H NMR (400 MHz, CDCl₃): δ □9.96(s, 1H), 8.89 (s, 1H), 8.44 (m, 2H), 7.46 (1H), 5.73 (s, 2H), 4.15 (m,1H), 3.73-3.43 (m, 3H), 1.35 (m, 1H), 1.01 (m, 2H), 0.03 (s, 9H);MS(ES): 479 (M+1).

Step 6:5-[(E)-(Hydroxyimino)methyl]-3-thienyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

A solution of3-(5-formyl-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(65 mg, 0.00014 mol) in methanol (2 mL, 0.05 mol) was treated withhydroxylamine hydrochloride (11 mg, 0.00016 mol) and potassiumbicarbonate (23 mg, 0.00023 mol). The reaction was stirred at roomtemperature for 4 hours. Water was added and the product was extractedwith ethyl acetate. The combined extracts were washed with saturatedsodium chloride, dried over magnesium sulfate, filtered and concentratedto give3-5-[(E)-(hydroxyimino)methyl]-3-thienyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrileas a semisolid oil (60 mg, 89.5%). (The crude product contained bothisomers of oxime and also both regioisomers of thiophene). MS (ES): 494(M+1).

Step 7:4-(2-Cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)thiophene-2-carbonitrile

To a mixture of3-5-[(E)-(hydroxyimino)methyl]-3-thienyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(70 mg, 0.0001 mol) in pyridine (1 mL, 0.01 mol), methanesulfonylchloride (100 μL, 0.001 mol) was added. The mixture was stirred at 60°C. for 2 hours. Water was added and the product was extracted with ethylacetate. The combined extracts were washed with 0.1 N HCl, brine, driedover magnesium sulfate, filtered and concentrated to give4-(2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)thiophene-2-carbonitrileas a crude product (30 mg, 44%). MS (ES): 476 (M+1).

Step 8:4-(2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)thiophene-2-carbonitriletrifluoroacetate

A mixture of4-(2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)thiophene-2-carbonitrile(50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) and TFA (1 mL, 0.01 mol) wasstirred for 1 hour. The starting material was consumed and the desiredmethyl hydroxy compound was formed. The mixture was concentrated invacuo to remove TFA. The crude intermediate was dissolved in methanol (3mL, 0.07 mol) and was treated with ethylenediamine (1 mL, 0.01 mol). Themixture was stirred overnight and concentrated in vacuo. The productswere purified by preparative HPLC eluting with ACN: water with 0.2% TFAto give two regioisomers, the title compound as an amorphous white solid(30 mg, 60%).

¹H NMR (500 MHz, DMSO): δ □8.95 (s, 1H), 8.76 (s, 1H), 8.48 (s, 1H),8.06 (s, 1H), 8.04 (s, 1H), 7.70 (d, 1H), 7.05 (d, 1H), 6.25 (m, 1H),3.80-3.60 (m, 2H); MS (ES): 346 (M+1).

Example 471:5-(2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)-thiophene-2-carbonitriletrifluoroacetate

Isolated as the second regioisomer from Example 470, the title compoundwas isolated as an amorphous white solid (4 mg, 8%). ¹H NMR (500 MHz,DMSO): δ □9.0 (s, 1H0, 8.75 (s, 1H), 8.50 (s, 1H), 7.95 (s, 1H), 7.65(s, 1H), 7.45 (s, 1H), 7.0 (d, 1H), 6.45 (m, 1H), 3.8 (dd, 2H); MS (ES):346 (M+1).

Example 472:3-[3-(Morpholin-4-ylcarbonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitriletrifluoroacetate

Step 1:3-(2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)benzoicacid

To a solution of methyl3-2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylbenzoate(50 mg, 0.0001 mol) (prepared as in Example 61) in methanol (2 mL, 0.05mol), lithium hydroxide (1 mg, 0.0001 mol) in water (1 mL, 0.06 mol) wasadded slowly. Water was added and also some 1N HCl was added until thesolution was slightly acidic. The aqueous layer was extracted with ethylacetate. The combined extracts were dried over magnesium sulfate,filtered and concentrated to give3-(2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)benzoicacid as a crude residue (35 mg, 72.0%). MS (ES): 489 (M+1).

Step 2:3-[3-(Morpholine-1-ylcarbonyl)phenyl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-4-yl]propanenitrile

To a solution of3-(2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)benzoicacid (40 mg, 0.00008 mol) in DMF (1 mL, 0.01 mol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (36 mg, 0.000095 mol) and DIPEA (30 μL, 0.0002 mol)were added. The reaction was stirred for 10 minutes and then morpholine(10 mg, 0.00012 mol) was added and the resulting mixture was stirred for3 hours. Water was added and the product was extracted with ethylacetate. The combined organic extracts were washed with 1N HCl, brine,dried over magnesium sulfate, filtered and concentrated to give3-[3-(morpholine-1-ylcarbonyl)phenyl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]propanenitrileas a crude (40 mg, 88%) product. MS (ES): 558 (M+1).

Step 3:3-[3-(Morpholin-4-ylcarbonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]propanenitriletrifluoroacetate

Using a procedure analogous to that of Example 61 for the removal of theSEM protecting group, the title compound was isolated as an amorphouswhite solid (18 mg, 50%). ¹H NMR (400 MHz, DMSO): δ □9.05 (s, 1H), 8.75(s, 1H), 8.44 (s, 1H), 7.85 (b, 1H), 7.665 (s, 1H), 7.55-7.35 (m, 3H),7.15 (s, 1H), 6.15 (m, 1H), 3.85 (m, 1H), 3.65-3.4 (m, 6H), 3.25 (m,2H), 3.05 (m, 1H); MS(ES): 428 (M+1).

Example 482:3-(5-Phenylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitriletrifluoroacetate

Step 1:3-(5-Phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

To a solution of3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(from Example 429) (60 mg, 0.0001 mol) in 1,4-dioxane (2 mL, 0.02 mol),phenylboronic acid (15 mg, 0.00012 mol) and sodium bicarbonate (30 mg,0.0003 mol) in water (0.5 mL, 0.03 mol) were added. The resultingmixture was degassed using nitrogen.Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.00001 mol) was addedand nitrogen was bubbled through the reaction again. The reaction washeated at 80° C. in oil bath for 1 hour. Water was added and the productwas extracted with ethyl acetate. The combined extracts were washed withsaturated sodium chloride, dried over magnesium sulfate, filtered andconcentrated to give3-(5-phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(50 mg, 80%) as a crude product. MS (ES): 522 (M+1).

Step 2:3-(5-Phenylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]propanenitriletrifluoroacetate

Using a procedure analogous to that of Example 61 for the removal of theSEM protecting group, the title compound was isolated as an amorphouswhite solid (20 mg, 40%). ¹H NMR (400 MHz, DMSO): δ □9.15 (s, 1H), 8.85(s, 1H), 8.80 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 7.85(b, 1H), 7.67 (m, 2H), 7.45 (m 2H), 7.43 (m, 1H), 7.15 (s, 1H), 6.25 (m1H), 3.95 (dd, 1H), 3.80 (dd, 1H), 3.0 (m, 1H); MS (ES): 392.1 (M+1)

Example 486:3-(5-Ethynylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitriletrifluoroacetate

Step 1:3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-5-[(trimethylsilyl)ethynyl]pyridin-3-ylpropanenitrile

To a solution of3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(from Example 429) (0.080 g, 0.00015 mol) in TEA (0.300 mL, 0.00215 mol)was degassed with nitrogen, and then copper(I) iodide (0.005 g, 0.00003mol), (trimethylsilyl)acetylene, andbis(triphenylphosphine)palladium(II)chloride were added. The reactionmixture was sealed in a tube and stirred at room temperature overnight.The resulting black solution was partitioned between water (10 mL) andethyl ether. The organic layer was washed with saturated sodiumchloride, dried over magnesium sulfate and concentrated in vacuo to give3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-5-[(trimethylsilyl)ethynyl]pyridin-3-ylpropanenitrileas a yellow oil (60 mg, 72.6), LCMS (M+1)⁺:542).

Step 2:3-(5-Ethynylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitriletrifluoroacetate

3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-5-[(trimethylsilyl)ethynyl]pyridin-3-ylpropanenitrile(0.050 g, 0.000092 mol) was dissolved in DCM (5.0 mL, 0.078 mol) and TFA(2.0 mL, 0.026 mol). The reaction mixture was stirred at roomtemperature, for 90 minutes and was concentrated in vacuo. The dryresidue dissolved in methanol cooled in an ice bath and a solution ofpotassium hydroxide (0.482 g, 0.00859 mol) in methanol (10 mL, 0.2 mol)was added. The reaction solution was stirred for 30 min was concentratedand the crude product was purified by preparative HPLC eluting with awater: ACN gradient with 0.2% TFA, to give the title compound as a whiteamorphous solid (15 mg, 35.85%). LCMS (M+1)⁺:340, ¹H NMR (400 MHz,DMSO-d₆): δ □12.1 (bs, 1H), 9.02 (s, 1H), 8.80 (s, 1H), 8.70 (m, 2H),8.48 (s, 1H), 8.00 (s, 1H), 7.80 (d, 1H), 7.15 (d, 1H), 6.20 (m, 1H),4.82 (s, 1H), 3.90 (m, 1H), 3.70 (m, 1H).

Example 488:3-[5-(Phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitriletrifluoroacetate

Step 1:3-[5-(Phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

To the3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(0.130 g, 0.000248 mol) from Example 429 Step 2, in dry 1,4-dioxane(1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). Thesolution was degassed with nitrogen, followed by addition of(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.007 g,0.00001 mol), bis(dibenzylideneacetone)palladium(0) (0.0036 g, 0.0000062mol), and benzenethiol (0.025 mL, 0.00025 mol). Again the solution waspurged with nitrogen. The reaction mixture in a sealed tube was heatedto reflux for 3 h. The reaction mixture was diluted with ethyl acetate,washed with water (2×), brine (1×), dried over magnesium sulfate,filtered, and the solvent was evaporated in vacuo. The crude product wastriturated with hexane-ethyl acetate 9:1 to yield3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(110 mg, 80%). LC/MS (M+H)⁺: m/z=554.2.

Step 2:3-[5-(Phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitriletrifluoroacetate

The3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(0.110 g, 0.000199 mol) was dissolved in DCM (5.0 mL, 0.078 mol) and TFA(2.0 mL, 0.026 mol), and the mixture was stirred at room temperature for1 hour. The solvent was removed in vacuo, and the resulting residue wasdissolved in methanol (5.0 mL, 0.12 mol), and ethylenediamine (0.1 mL,0.002 mol) was added. This reaction mixture was stirred at roomtemperature overnight. The mixture was concentrated in vacuo, and thecrude product was purified by LCMS (pH=2) to yield the title compound asan amorphous solid (62 mg, 58.07%).

¹H NMR (400 MHz, DMSO): δ □12.80 (s), 9.10 (s) 8.87 (d), 8.60 (s), 8.50(s), 8.43 (s), 7.82 (s), 7.78 (m), 7.39 (m), 7.25 (m), 7.18 (d), 6.20(m), 3.84 (m), 3.70 (m). LC/MS (M+H)⁺: m/z=424.15

Example 491:3-(5-Morpholin-4-ylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

Step 1: 4-(5-Bromopyridin-3-yl)morpholine

To a solution of [3,5-dibromopyridine (1000 mg, 0.004 mol) in1,4-dioxane (8 mL, 0.1 mol), morpholine (400 mg, 0.004 mol) and sodiumtert-butoxide (400 mg, 0.004 mol) were added. The reaction was bubbledwith nitrogen. Tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.0002mol) was added and nitrogen was bubbled through for couple of minutes.The mixture was heated at 80° C. overnight. The reaction was allowed tocool to rt and was then partitioned between water and ethyl acetate. Theorganic layer was washed with saturated sodium chloride, dried overmagnesium sulfate, filtered and concentrated to give a crude residue.The crude product was purified by FCC on silica gel eluting with 1:1,EtOAC:Hexane gave to give 4-(5-bromopyridin-3-yl)morpholine as a viscousoil (400 mg, 40%). ¹H NMR (400 MHz, CDCl3): δ □8.2 (s, 1H), 8.1 (s, 1H),7.2 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H).

Step 2: 5-Morpholin-4-ylnicotinaldehyde

A solution of 4-(5-bromopyridin-3-yl)morpholine (100 mg, 0.0004 mol) inether (2 mL, 0.02 mol) cooled at −78° C. was treated with 2.5 Mn-butyllithium in hexane (0.2 mL) and was stirred for 1 h. To thismixture was added DMF (0.5 mL, 0.006 mol) dropwise. The reaction wasquenched with water and extracted with ethyl acetate. The combinedorganic layers were washed with saturated sodium chloride, dried overmagnesium sulfate, filtered and concentrated to give5-morpholin-4-ylnicotinaldehyde (70 mg, 90%) as a crude product. ¹H NMR(400 MHz, CDCl3): δ□ 10.1 (s, 1H), 8.0 (s, 2H), 7.6 (s, 1H), 3.8 (m,4H), 3.2 (m, 4H).

Step 3: (2E)-3-(5-Morpholin-4-ylpyridin-3-yl)acrylonitrile

To a solution of diethyl cyanomethylphosphonate (70 mg, 0.0004 mol) inTHF (2 mL, 0.02 mol) cooled at 0° C. was added 1.0 M potassiumtert-butoxide in THF (0.50 mL) dropwise. The cold bath was removed andthe reaction was warmed to room temperature over 30 minutes. Thereaction was cooled to 0° C. and a solution of5-morpholin-4-ylnicotinaldehyde (70 mg, 0.0004 mol) in THF (2 mL, 0.02mol) was added dropwise. The reaction was stirred at room temperaturefor 4 h, quenched with water and extracted with ethyl acetate. Thecombined organic layers were washed with saturated sodium chloride,dried over magnesium sulfate, filtered and concentrated to give(2E)-3-(5-morpholin-4-ylpyridin-3-yl)acrylonitrile (75 mg, 100%) as amixture of isomers; LC/MS: 216 (M+1).

Step 4:3-(5-Morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and(2E)-3-(5-morpholin-4-ylpyridin-3-yl)acrylonitrile (70 mg, 0.0003 mol)(mixture of isomers), DBU (50 μL, 0.0003 mol) was added and theresulting mixture was stirred overnight. The mixture was partitionedbetween water and ethyl acetate. The combined organic layers were washedwith saturated sodium chloride, dried over magnesium sulfate, filteredand concentrated to give3-(5-morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(200 mg, 100%) as a crude product; L/MS=531 (M+1).

Step 5:3-(5-Morpholin-4-ylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile

Using a procedure analogous to Example 61 for the removal of the SEMprotecting the title compound was isolated as an amorphous white solid(18 mg, 50%). ¹H NMR (400 MHz, DMSO): δ□ 8.8 (s, 1H), 8.6 (s, 1H), 8.4(s, 1H), 8.2 (s, 1H), 8.0 (s, 1H), 7.6 (d, 1H), 7.4 (m, 1H), 6.9 (d,1H), 6 (m, 1H), 3.8 (dd, 1H), 3.7 (m, 4H), 3.6 (dd, 1H), 3.1 (m, 4H);LC/MS: 401 (M+1).

Example 496:3-[5-(Phenylsulfinyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrileand Example 497:3-[5-(Phenylsulfonyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

To the solution of3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitriletrifluoroacetate (0.050 g, 0.000093 mol) from Example 488, Step 2, inTHF (1.0 mL, 0.012 mol) was added MCPBA (0.022 g, 0.00013 mol) (0.031 gof 77% in water), in a water ice bath. The reaction mixture was stirredfor 1 h at room temperature. The crude products were purified by LCMS(pH=10). Two peaks were collected:

#1—to yield3-[5-(phenylsulfinyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(8 mg, 19.57%). ¹H NMR (400 MHz, DMSO): δ □12.1 (s), 8.89 (d), 8.80 (d),8.70 (s), 8.62 (s), 8.40 (s), 8.19 (s), 7.70 (m), 7.58 (s), 7.42 (m),6.90 (s), 6.20 (m), 3.82 (m), 3.65 (m). LC/MS (M+H)⁺: m/z=440.0

#2—to yield3-[5-(phenylsulfonyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(21 mg, 50%). ¹H NMR (400 MHz, DMSO): δ □12.1 (s), 9.10 (s), 8.86 (m),8.61 (s), 8.40 (m), 7.98 (m), 7.62 (m), 7.58 (m), 6.90 (s), 6.20 (m),3.82 (m), 3.65 (m). LC/MS (M+H)⁺: m/z=456.0

Example 498:3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentan-1-ol

Step 1:3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal

To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(100 mg, 0.0003 mol) in ACN (2 mL, 0.04 mol) and DBU (50 μL, 0.0003mol), the (2E)-pent-2-enal (4.0E1 mg, 0.00048 mol) in 1 ml ACN was addeddrop wise. The reaction was stirred for 1 h, and then water was addedand the resulting mixture extracted with ethyl acetate. The combinedorganic layers were washed with saturated sodium chloride, dried overmagnesium sulfate, filtered and concentrated to give the crude as thehydrated product form. LC/MS (M+H)⁺: m/z=400.

Step 2:3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentan-1-ol

A mixture of[3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal(50 mg, 0.0001 mol) in methanol (2 mL, 0.05 mol) was treated with sodiumtetrahydroborate (8 mg, 0.0002 mol). The mixture was stirred at roomtemperature for 1 h, and then water was added and the product wasextracted with ethyl acetate. The combined organic layers were washedwith saturated sodium chloride, dried over magnesium sulfate, filteredand concentrated to give the desired product as an oil. LC/MS (M+H)⁺:m/z=402.

Step 3

Using a procedure analogous to Example 61 for the removal of the SEMprotecting group the title compound was isolated as an amorphous whitesolid (6 mg, 20%). ¹H NMR (400 MHz, DMSO): δ□ 8.65 (d, 1H), 8.60 (d,1H), 7.55 (s, 1H), 6.95 (s, 1H), 4.50 (b, 1H), 4.4 (m, 1H), 3.4 (m, 1H),3.2 (m, 1H), 2.1 (m, 1H), 1.8-2.0 (m, 3H), 0.7 (t, 3H); LC/MS (M+H)⁺:m/z=272.

Example 499: Methyl3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentyl carbonate

Step 1: Methyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentylcarbonate

To a solution of[3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentan-1-ol(50 mg, 0.0001 mol) from Example 498 Step 2 in pyridine (1 mL, 0.01mol), methyl chloroformate (30 μL, 0.0003 mol) was added. The reactionwas stirred for 3 h, water was added and the product was extracted withethyl acetate. The combined organic layers were washed 1N HCl, brine,dried over magnesium sulfate, filtered and concentrated to give methyl3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentylcarbonate as a semisolid residue (30 mg, 50%). LC/MS (M+H)⁺: m/z=460.

Step 2

Using a procedure analogous to Example 61 for the removal of the SEMprotecting the title compound was isolated as an amorphous white solid(8 mg, 20%). ¹H NMR (400 MHz, DMSO): δ □12.0 (b, 1H), 8.65 (d, 1H), 8.35(s, 1H), 7.65 (b, 1H), 7.600 (s, 1H), 7.0 (s, 1H), 4.4 (m, 1H), 4.0 (m,1H), 3.8 (m, 1H), 3.6 (s, 3H), 2.1 (m, 1H), 2.2 (m, 1H), 1.95 (m, 2H),0.75 (t, 3H); LC/MS (M+H)⁺: m/z=330.

Example 500(a):(1E)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanaloxime

Step 1:(1E)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanaloxime

To a solution of3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal(60 mg, 0.0002 mol) from Example 498, Step 2 in methanol (2 mL, 0.05mol) was added hydroxylamine hydrochloride (16 mg, 0.00022 mol) andpotassium bicarbonate (22 mg, 0.00022 mol). The reaction was stirred atroom temperature for 2 h, water was added and the product was extractedwith ethyl acetate. The combined extracts were washed with saturatedsodium chloride, dried over magnesium sulfate, filtered and concentratedto give(1E)-3-[4-(7-[2-(trimethyl-silyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanaloxime as a semisolid residue (50 mg, 80%). LC/MS (M+H)⁺: m/z=415.

Step 2

Using a procedure analogous to Example 61 for the removal of the SEMprotecting the title compound was isolated as an amorphous white solid.¹H NMR (400 MHz, DMSO): δ□□ 12.0 (b, 1H), 8.6 (m, 2H), 8.2 (m, 1H), 7.5(d, 1H), 7.1 and 6.5 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.6-2.8 (m, 2H),1.8 (m, 2H), 0.65 (t, 3H); LC/MS (M+H)⁺: m/z=285.

Example 501(a):(1E)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanalO-methyloxime and Example 502(a):(1Z)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanalO-methyloxime

Step 1:(E)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanalO-methyloxime and (1 Z)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanalO-methyloxime

To a solution of3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal(70 mg, 0.0002 mol) in methanol (2 mL, 0.05 mol) was added methoxylaminehydrochloride (19 mg, 0.00022 mol) and potassium bicarbonate (22 mg,0.00022 mol). The reaction was stirred at room temperature for 2 h,water was added and the product was extracted with ethyl acetate. Thecombined extracts were washed with saturated sodium chloride, dried overmagnesium sulfate, was filtered and was concentrated to give3-[4-(7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanalO-methyloxime as a mixture of isomers (70 mg, 90%) crude product. LC/MS(M+H)⁺: m/z=429.

Step 2

Using a procedure analogous to Example 61 for the removal of the SEMprotecting the title compound was isolated as an amorphous white solid(4 mg, 25%). Isomer 1, ¹H NMR (400 MHz, DMSO): δ □□8.7 (s, 2H), 8.3 (s,1H), 7.6 (s, 1H), 7.3 (t, 1H), 7.0 (s, 1H), 4.6 (m, 1H), 3.3 (s, 3H),2.8 (m, 2H), 1.9 (m, 2H), 0.8 (t, 3H); LC/S (M+H)⁺: m/z=299. Isomer 2 (3mg, 22%), ¹H NMR (400 MHz, DMSO): δ□□ 8.7 (s, 2H), 8.3 (s, 1H), 7.6 (s,1H), 7.0 (s, 1H), 6.7 (t, 1H), 4.5 (m, 1H), 3.3 (s, 3H), 2.8-3.0 (m,2H), 1.9 (m, 2H), 0.8 (t, 3H); LC/MS (M+H)⁺: m/z=299.

Example 503:4-[1-(4,4-Dibromo-1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidinetrifluoroacetate

Step 1:4-[1-(4,4-Dibromo-1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

To a solution of3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal(300 mg, 0.0008 mol) in DCM (4 mL, 0.06 mol) cooled at 0° C.,triphenylphosphine (800 mg, 0.003 mol) and carbon tetrabromide (500 mg,0.002 mol) were added. The reaction was stirred at 0° C. for 10 min,water was added and extracted with ethyl acetate. The combined organicextracts were washed with saturated sodium chloride, dried overmagnesium sulfate, filtered and concentrated. The crude product waspurified by prep LC-MS (ACN, water, NH₄OH) to give4-[1-(4,4-dibromo-1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidineas an amorphous solid (50 mg, 10%). ¹H NMR (400 MHz, CDCl3): δ □□8.9 (s,2H), 8.4 (s, 1H), 8.3 (s, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 6.9 (m, 1H),6.4 (m, 1H), 5.7 (s, 2H), 4.2 (m, 1H), 3.6 (m, 2H), 2.8 (m, 2H), 2.1 (m,1H), 2.0 (m, 1H), 1.0 (m, 5H), LC/MS (M+H)⁺: m/z=556

Step 2

Using a procedure analogous to Example 61 for the removal of the SEMprotecting the title compound was isolated as an amorphous white solid(8 mg, 40%). ¹H NMR (400 MHz, DMSO): δ □□8.8 (s, 2H), 8.4 (s, 1H), 7.7(b, 1H), 7.2 (b, 1H), 6.5 (t, 1H), 4.4 (m, 1H), 2.6 (m, 2H), 1.8 (m,2H), 0.8 (t, 3H); LC/MS (M+H)⁺: m/z=: 426.

Example 506:4-[1-(1-Ethylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate

Step 1:4-[1-(1-Ethylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

A solution of4-[1-(4,4-dibromo-1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(20 mg, 0.00004 mol) (from Example 503 Step 1) in THF (1 mL, 0.01 mol)at −78° C. was treated with 2.5 M n-butyllithium in hexane (0.032 mL).The mixture was stirred at −78° C. for 1 h and then at room temperaturefor 1 h. The reaction was quenched with water (1 mL, 0.06 mol) and 1NHCl. The reaction was partitioned between water and ethyl acetate. Theorganic extract was washed with saturated sodium chloride, dried overmagnesium sulfate, filtered and concentrated to give4-[1-(1-ethylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7-[2-(tri-methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidineas a semisolid (12 mg, 80%). LC/MS (M+H)⁺: m/z=396.

Step 2

Using a procedure analogous to Example 61 for the removal of the SEMprotecting the title compound was isolated as an amorphous white solid(4 mg, 30%). ¹H NMR (400 MHz, DMSO): δ□□12.2 (b, 1H), 8.8 (s, 2H), 8.4(s, 1H), 7.6 (s, 1H), 7.1 (s, 1H), 4.4 (m, 1H), 2.8 (m, 3H), 1.9 (m,2H), 0.8 (t, 3H); LC/MS(M+H)⁺: m/z=266.

Example 516:(R)-3-[3-(Ethylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrileand(S)-3-[3-(Ethylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile

Step 1: 1-Bromo-3-(ethylthio)benzene

Iodoethane (0.46 mL, 0.0058 mol) was added to a suspension of3-bromothiophenol (0.50 mL, 0.0048 mol), ACN (7.11 mL, 0.136 mol) andpotassium carbonate (2.0 g, 0.014 mol). The reaction was stirred for 2 hat rt, was diluted with ethyl acetate and filtered to remove the solids.The reaction was concentrated in vacuo to give1-bromo-3-(ethylthio)benzene as a colorless oil 1.0 gm, 100%

Step 2: 1-Bromo-3-(ethylsulfonyl)benzene

The MCPBA (2.37 g, 10.6 mmol) was added to a solution of1-bromo-3-(ethylthio)benzene (1.00 g, 4.80 mmol) in DCM (10 ml, 156mmol) cooled to 0° C. The reaction was stirred for 1 h and then wasdiluted with water and extracted with ethyl acetate three times. Thecombined organic layers were dried with magnesium sulfate, filtered, andconcentrated in vacuo. The resulting crude residue was purified by flashcolumn chromatography with a hexane: ethyl acetate gradient to give1-bromo-3-(ethylsulfonyl)benzene as a colorless oil 1.1 gm 92%, ¹H NMR(300 MHz, CDCl₃): δ□8.09 (m, 1H), 7.85 (d, 1H), 7.78 (d, 1H) 7.45 (t,1H), 3.14 (q, 2H), 1.25 (t, 3H).

Step 3: (2E & Z)-3-[3-(Ethylsulfonyl)phenyl]acrylonitrile

1-Bromo-3-(ethylsulfonyl)benzene (1.3 g, 0.0052 mol) was dissolved inthe DMF (15.0 mL, 0.194 mol) and 2-propenenitrile (0.68 mL, 0.010 mol),TEA (1.4 mL, 0.010 mol) and triphenylphosphine (0.23 g, 0.00089 mol)were added. The resulting solution was degassed with nitrogen, andpalladium acetate (0.07 g, 0.0003 mol) was added. Again the reaction wasdegassed with nitrogen and then heated to 110° C. in a sealed tube for 8hrs. The reaction was complete by HPLC, and was then allowed to cool tort and then partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over magnesium sulfate andconcentrated. The product was purified by FCC on silica gel eluting witha hexane; ethyl acetate gradient to give(2E&Z)-3-[3-(ethylsulfonyl)phenyl]acrylonitrile as an amber oil (1.1 gm,92%) LC/MS (M+H)⁺: m/z=222.

Step 4:3-[3-(Ethylsulfonyl)phenyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]propanenitrile

The (2E&Z)-3-[3-(ethylsulfonyl)phenyl]acrylonitrile (1.0 g, 0.0045 mol)was combined with4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(1.3 g, 0.0041 mol) and DBU (0.61 mL, 0.0041 mol) in ACN (10.0 mL, 0.191mol) under nitrogen at rt. The reaction was stirred at rt for 24 h. Thiswas partitioned between ethyl acetate and water, and 0.1N HCl was addedto adjust the pH to 7. The combined organic extracts were washed withbrine, dried over magnesium sulfate and concentrated to give a crudeoil. The product was purified by FCC on silica gel eluting with ahexane: ethyl acetate gradient to give3-[3-(ethylsulfonyl)phenyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrileas an oil (1.5 gm, 68%). LC/MS (M+H)⁺: m/z=537. The oil was a racimate,which was separated by chiral column chromatography (Chiracel OD-H,eluting with ethanol:methanol:hexane 30:30:40, Rt 13.2 and 17.1 minutes)to give the two enantiomers, each as a glass (0.51 gm) LC/MS (M+H)⁺:m/z=537, ¹H NMR (300 MHz, CDCl₃): δ 8.89 (s, 1H), 8.45 (s, 1H), 8.35 (s,1H), 8.09 (s, 1 h), 8.05 (d, 1H), 7.75 (d, 1H), 7.71 (t, 1H), 7.45 (d,1H), 6.83 (d, 1H), 5.85 (t, 1H), 5.75 (s, 2H), 3.78-3.42 (m, 4H), 3.18(m, 2H), 1.35 (t, 3H), 0.97 (t, 2H), 0.05 (s, 9H).

Step 5

Using a procedure analogous to Example 61 for the removal of the SEMprotecting group the title compounds were prepared to give isomer #1 asan amorphous white solid (300 mg, 80%). ¹H NMR (400 MHz, DMSO): δ □□9.1(s, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 8.0 (s, 1H), 7.6-7.9 (m, 4H), 7.1 (s,1H), 6.3 (m, 1H), 3.9 (m, 1H), 3.7 (m, 1H) 3.2 (q, 2H), 1.0 (t, 3H);MS(ES) (M+H)⁺: m/z=407.

Using a procedure analogous to Example 61 for the removal of the SEMprotecting group the title compounds were prepared to give isomer #2 asan amorphous white solid (300 mg, 80%).

¹H NMP (400 MHz, DMSO): δ □□9.1 (s, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 8.0(s, 1H), 7.6-7.9 (m, 4H), 7.1 (s, 1H), 6.3 (m, 1H), 3.9 (m, 1H), 3.7 (m,1H) 3.2 (q, 2H), 1.0 (t, 3H); MS(ES) (M+H)⁺: m/z=407.

Example 526:4-[1-(1-Ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine

Step 1:4-[1-(1-Ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidine

To an ice cooled solution of methyl triphenylphosphonium bromide (100mg, 0.0004 mol) in THF (2 mL, 0.02 mol) was added 0.5 M potassiumbis(trimethylsilyl)amide in toluene (0.8 mL). The mixture was stirredfor 1 h at 0° C. ice bath, and was then cooled to −78° C. and treatedwith3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal(80 mg, 0.0002 mol) (from Example 498). The reaction was stirred at −78°C. and gradually was warmed to room temperature overnight. The reactionwas partitioned between water and ethyl acetate. The organic layer waswashed with saturated sodium chloride, dried over magnesium sulfate,filtered and concentrated to give4-[1-(1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine150 mg as a crude product. LC/MS=398 (M+1).

Step 2:4-[1-(1-Ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine

Using a procedure analogous to Example 61 for the removal of the SEMprotecting group the title compound was isolated as an amorphous whitesolid (25 mg, 1%). ¹H NMR (400 MHz, DMSO): δ □8.6 (s, 2H), 8.2 (s, 1H),7.4 (s, 1H), 6.9 (s, 1H), 5.8 (m, 1H), 5.0 (dd, 2H), 4.2 (m, 1H),2.4-2.6 (m, 2H), 1.7-1.9 (m, 2H), 0.6 (t, 3H); LC/MS: 268 (M+1).

Example 500: (3R)- and(3S)-4,4,4-Trifluoro-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]butanenitrile

Step 1. 4-Chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine

A mixture of 4-chloropyrrolo[2,3-d]pyrimidine (2.00 g, 0.0130 mol) andethyl orthoformate (25 mL, 0.15 mol) was heated to reflux for 2 hours.The solvent was evaporated, and the residue was purified by flash columnchromatography (eluting with ethyl acetate/hexanes) to yield the desiredproduct (1.13 g, 34%).

¹H NMR (400 MHz, CDCl₃): δ 8.63 (s, 1H), 7.58 (d, 1H), 6.71 (s, 1H),6.65 (d, 1H), 3.77-3.67 (m, 2H), 3.58-3.49 (m, 2H), 1.23 (t, 3H), 1.23(t, 3H).

Step 2.7-(Diethoxymethyl)-4-(1H-pyrrol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

To a degassed solution of4-chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.13 g, 0.00442mol) and 1-(triisopropylsilyl)-3-boronic acid (1.00 g, 0.00374 mol) andsodium carbonate (0.396 g, 0.00374 mol) in 1,2-dimethoxyethane (15 mL)and water (3 mL) was added tetrakis(triphenylphosphine)palladium(0)(0.22 g, 0.00019 mol). This mixture was stirred at ambient temperaturefor 2 hours, and then was heated to reflux for 4 hours. The mixture wasthen cooled, concentrated, and purified by flash column chromatography(eluting with ethyl acetate/hexanes) to afford a residue as an oil. ACNwas added to the residue, and the product which precipitated wasfiltered off and washed with a small quantity of ACN (165 mg, 13%).

¹H NMR (400 MHz, D₆-dmso): δ □11.44 (br s, 1H), 8.66 (s, 1H), 7.80-7.78(m, 1H), 7.58 (d, 1H), 7.03 (d, 1H), 6.94 (dd, 1H), 6.90 (dd, 1H), 6.75(s, 1H), 3.74-3.65 (m, 2H), 3.59-3.50 (m, 2H), 1.15 (t, 6H); MS(ES):M+H=287.

Step 3

To a solution of7-(diethoxymethyl)-4-(1H-pyrrol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.125g, 0.436 mmol) and 4,4,4-trifluorobut-2-enenitrile (0.0476 mL, 0.480mmol) in ACN (1 mL) was added DBU (0.0653 mL, 0.436 mmol). TFA (0.5 mL)was added and the mixture was stirred for 1 hour. The TFA and solventwas removed in vacuo. The residue was purified by preparative-HPLC/MS(C-18 eluting with a gradient of H₂O/ACN containing 0.15% NH₄OH) toafford the product (102 mg, 76%). Where desired, the enantiomers wereseparated in substantially pure form by chiral HPLC (AD-H, 20%EtOH/Hexane).

¹H NMR (300 MHz, D₆-dmso): δ 12.05 (br s, 1H), 8.65 (s, 1H), 8.04 (s,1H), 7.56 (dd, 1H), 7.21 (t, 1H), 7.02 (dd, 1H), 6.93 (dd, 1H),5.89-5.74 (m, 1H), 3.95 (dd, 1H), 3.66 (dd, 1H); MS(ES): M+H=306.

The analog in Table 12 was prepared in racemic form according to thesame procedure, using a different conjugate acceptor and with theexception that in the conjugate addition in Step 3, the reaction wascarried out at 40° C. for 3 days.

TABLE 12

Method of MS preparation Ex. (ES) and chiral No. Name R (M + 1)separation 501 3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- CH₃ 252 Ex. 500,1H-pyrrol-1-yl]butanenitrile enantiomers not sepa- rated

The following compounds in Table 13 were prepared as indicated in thecolumn labeled “Method of Prep.” and the details of certain exemplarysynthetic procedures are provided following Table 13.

TABLE 13

Method Ex. # R¹ R² M + 1 Name of prep. 601 CH₂CN

502 N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)- 3-(trifluoromethyl)benzamide Ex 468 602 H

463 N-(3-{[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}phenyl)-3- (trifluoromethylbenzamide Ex 468 603 CH₂CN SO₂CH₃393 3-[3-(methylsulfonyl)phenyl]-3- Ex 516 ee#1[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]- propanenitrile603 CH₂CN SO₂CH₃ 393 3-[3-(methylsulfonyl)phenyl]-3- Ex 516 ee#2[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1-yl]- propanenitrile604 H

431 N-(3-{[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}phenyl)benzene- sulfonamide Ex 469 605 H

463 3-{[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}-N-[3-(trifluoro- methyl)phenyl]benzamide Ex 472 606 ee#1CH₂CN

422 3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N,N- dimethylbenzenesulfonamide Ex 649 606 ee#2CH₂CN

422 3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N,N- dimethylbenzenesulfonamide Ex 649 607 CH₂CN

484 N-benzyl-3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}benzene- sulfonamide trifluoroacetate Ex 649 608CH₂CN

448 N-benzyl-3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}- benzamide Ex 472 609 CH₂CN

434 3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N- phenylbenzamide trifluoroacetate Ex 472 610CH₂CN

502 3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-[3- (trifluoromethyl)phenyl- benzamidetrifluoroacetate Ex 472 611 H

420 N-(3-cyanophenyl)-3-{[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]- methyl}benzamide Ex 472 612 H

409 N-benzyl-3-{[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}benzamide Ex 472 613 H

445 N-1-naphthyl-3-{[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}- benzamide Ex 472 614 H

445 N-2-naphthyl-3-{[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}- benzamide Ex 472 615 H

445 N-(3-{[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}phenyl)-2- naphthamide trifluoroacetate Ex 468 616 H

445 N-(3-{[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}phenyl)-1- naphthamide trifluoroacetate Ex 468 617 H

409 2-phenyl-N-(3-{[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}- phenyl)acetamide trifluoroacetate Ex 468 618 H

429 3-chloro-N-(3-{[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}phenyl)- benzamide trifluoroacetate Ex 468 619 CH₂CN

484 N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)- 2-naphthamide trifluoroacetate Ex 468 620CH₂CN

484 N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)- 1-naphthamide trifluoroacetate Ex 468 621CH₂CN

448 N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-ethyl}phenyl)- 2-phenylacetamide trifluoroacetate Ex468 622 CH₂CN

459 3-cyano-N-(3-{2-cyano-1-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]- ethyl}phenyl)benzamide trifluoroacetate Ex 468 623CH₂CN

434 N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}- phenyl)benzamide trifluoroacetate Ex 468 624CH₂CN

502 N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)- 4-(trifluoromethyl)benzamidetrifluoroacetate Ex 468 625 CH₂CN

449 N-(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)- N′-phenylurea trifluoroacetate Ex 480 626CH₂CN

502 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-[4- (trifluoromethyl)phenyl]- benzamidetrifluoroacetate Ex 472 627 CH₂CN

448 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(4- methylphenyl)benzamide trifluoroacetate Ex 472628 CH₂CN

459 N-(4-cyanophenyl)-3-{2-cyano- 1-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1- yl]ethyl}benzamide trifluoroacetate Ex 472629 CH₂CN

484 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-2- naphthylbenzamide trifluoro- acetate Ex 472 630CH₂CN

484 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-1- naphthylbenzamide tri- fluoroacetate Ex 472 631CH₂CN

386 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N,N- dimethylbenzamide tri- fluoroacetate Ex 472 632CH₂CN

435 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-pyridin- 3-ylbenzamide trifluoroacetate Ex 472 633CH₂CN

448 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-methyl- N-phenylbenzamide trifluoroacetate Ex 472634 CH₂CN

440 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N- cyclohexylbenzamide tri- fluoroacetate Ex 472 635CH₂CN

526 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(4- phenoxyphenyl)benzamide trifluoroacetate Ex472 636 CH₂CN

459 N-(3-cyanophenyl)-3-{2-cyano- 1-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1- yl]ethyl}benzamide trifluoroacetate Ex 472637 CH₂CN

510 N-biphenyl-4-yl-3-{2-cyano-1- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1- yl]ethyl}benzamide trifluoroacetate Ex 472638 CH₂CN

468 N-(4-chlorophenyl)-3-{2-cyano- 1-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1- yl]ethyl}benzamide trifluoroacetate Ex 472639 CH₂CN

462 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(3,4- dimethylphenyl)benzamide trifluoroacetate Ex472 640 CH₂CN

464 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(3- methoxyphenyl)benzamide trifluoroacetate Ex472 641 CH₂CN

464 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(4- methoxyphenyl)benzamide trifluoroacetate Ex472 642 CH₂CN

425 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-isoxazol- 3-ylbenzamide trifluoroacetate Ex 472643 CH₂CN

484 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-methyl- N-phenylbenzenesulfonamide Ex 649 644CH₂CN

436 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N- propylbenzenesulfonamide Ex 649 645 CH₂CN

470 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N- phenylbenzene sulfonamide Ex 649 646 CH₂CN

520 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-2- naphthylbenzene- sulfonamide Ex 649 647 CH₂CN

434 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N- cyclopropylbenzene- sulfonamide Ex 649 648 CH₂CN

462 3-[3-(piperidin-1-ylsulfonyl)- phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol- 1-yl]propanenitrile Ex 649 649 CH₂CN

464 3-[3-(morpholin-4-ylsulfonyl)- phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol- 1-yl]propanenitrile Ex 649 650 CH₂CN

484 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(4- methylphenyl)benzene- sulfonamidetrifluoroacetate Ex 649 651 CH₂CN

498 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(3,4- dimethylphenyl)benzene- sulfonamidetrifluoroacetate Ex 649 652 CH₂CN

500 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(3- methoxyphenyl)benzene- sulfonamidetrifluoroacetate Ex 649 653 CH₂CN

500 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(4- methoxyphenyl)benzene- sulfonamidetrifluoroacetate Ex 649 654 CH₂CN

494 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(3,5- dimethoxyphenyl)benzamide trifluoroacetateEx 472 655 CH₂CN

477 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-[4- (dimethylamino)phenyl]- benzamidetrifluoroacetate Ex 472 656 CH₂CN

469 3-[3-(benzylsulfonyl)phenyl]-3- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile Ex 516 657 CH₂CN

437 3-[3-(benzylthio)phenyl]-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile Ex 514 658 CH₂CN

494 4-{[(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}phenyl)- sulfonyl]methyl}benzonitrile Ex 516 659CH₂CN

408 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-methyl- benzenesulfonamide Ex 649 660 CH₂CN

520 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-dlpyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-1- naphthylbenzenesulfonamide Ex 649 661 CH₂CN

546 N-biphenyl-4-yl-3-{2-cyano-1- [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}- benzenesulfonamide Ex 649 662 CH₂CN

518 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-[4- (trifluoromethoxy)phenyl]- benzamidetrifluoroacetate Ex 472 663 CH₂CN

464 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(2- methoxyphenyl)benzamide trifluoroacetate Ex472 664 CH₂CN

421 3-[3-(benzoloxy)phenyl]-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]- propanenitrile Ex 514 665 CH₂CN

476 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N- cyclohexylbenzenesulfonamide trifluoroacetate Ex649 666 CH₂CN

510 3-[3-(3,4-dihydroisoquinolin- 2(1H)-ylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-1H-pyrazol-1-yl]propane- nitriletrifluoroacetate Ex 649 667 CH₂CN

452 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(2- methoxyethyl)benzene- sulfonamidetrifluoroacetate Ex 649 668 CH₂CN

450 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N,N- diethylbenzenesulfonamide Ex 649 669 CH₂CN

491 3-{3-[(4-ethylpiperazin-1-yl)- sulfonyl]phenyl]-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 649670 CH₂CN

514 N-1,3-benzodioxo1-5-yl-3-{2- cyano-1-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1- yl]ethyl]benzenesulfonamide Ex 649 671CH₂CN

499 3-{3-[(3-methoxybenzyl)- sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]-propanenitrile Ex 516672 CH₂CN

499 3-{3-[(4-methoxybenzyl)- sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]-propanenitrile Ex 516673 CH₂CN

492 3-{3-[(2,6-dimethylmorpholin- 4-yl)sulfonyl]phenyl }-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-1H-pyrazol-1-yl]- propanenitrile Ex649 674 CH₂CN

476 3-{3-[(4-oxopiperidin-1-yl)- sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitriletrifluoroacetate Ex 649 675 CH₂CN

421 3-[3-(isopropylsulfonyl) phenyl]-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1- yl]propanenitrile trifluoroacetate Ex 516676 CH₂CN

475 3-{3-[(cyclohexylmethyl)- sulfonyl]phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]-propanenitriletrifluoroacetate Ex 516 677 CH₂CN

516 3-[3-(octahydroisoquinolin- 2(1H)-ylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-1H-pyrazol-1-yl]propane- nitriletrifluoroacetate Ex 649 678 CH₂CN

483 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(2- phenylethyl)benzene sulfonamidetrifluoroacetate Ex 516 679 CH₂CN

448 3-[3-(pyrrolidin-1-ylsulfonyl)- phenyl]-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1- yl]propanenitrile Ex 649 680 CH₂CN

498 N-benzyl-3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N- methylbenzenesulfonamide Ex 649 681 CH₂CN

494 3-{[(3-{2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}- phenyl)sulfonyl]methyl}- benzonitrile Ex 516 682CH₂CN

519 3-{3-[(2-naphthylmethyl)- sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 516 683CH₂CN

483 3-{3-[(1-phenylethyl)sulfonyl]- phenyl}-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1- yl]propanenitrile Ex 516 684 CH₂CN

507 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-(2- morpholin-4-ylethyl)- benzenesulfonamide Ex649 685 CH₂CN

494 N-(2-aminoethyl)-2-{[(3-{2- cyano-1-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1- yl]ethyl}phenyl)sulfonyl]- amino}acetamideEx 649 686 CH₂CN

498 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-[(1S)-1- phenylethyl]benzenesulfonamide Ex 649 687ee#1 CH₂CN

434 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-phenyl- benzamide trifluoroacetate Ex 472 687 ee#2CH₂CN

434 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-phenyl- benzamide trifluoroacetate Ex 472 688CH₂CN

478 3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N- (tetrahydrofuran-2-yl- methyl)benzenesulfonamideEx 472 689 CH₂CN

433 3-{3-[(cyclopropylmethyl) sulfonyl]phenyl}-3-[4-(7 H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitriletrifluoroacetate Ex 516 690 CH₂CN

477 3-{3-[(4-methylpiperazin-1-yl)- sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 472 691CH₂CN

561 1-[(3-{2-cyano-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}- phenyl)sulfonyl]-N,N-diethyl-piperidine-3-carboxamide Ex 472 692 CH₂CN

496 3-{3-[(1-oxidothiomorpholin-4- yl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 472 693CH₂CN

463 3-[3-(piperazin-1-ylsulfonyl)- phenyl]-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1- yl]propanenitrile Ex 472 694 CH₂CN

480 3-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-[3-(thiomorpholin-4-yl- sulfonyl)phenyl]propanenitrile Ex 472 695CH₂CN

478 3-{3-[(4-hydroxypiperidin-1-yl)- sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitriletrifluoroacetate Ex 472 696 CH₂CN

435 3-[3-(isobutylsulfonyl)phenyl]-3- [4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-1H-pyrazol-1-yl]propane- nitrile trifluoroacetate Ex 516 697 CH₂CN

477 3-[4-(7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-{3-[(tetrahydro-2H-pyran- 4-ylmethyl)sulfonyl]-phenyl}propanenitrile trifluoroacetate Ex 516 698 CH₂CN

437 3-{3-[(2-methoxyethyl)sulfonyl]- phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1- yl]propanenitrile trifluoroacetate Ex516 699 CH₂CN

459 3-{3-[(3-furylmethyl)sulfonyl]- phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1- yl]propanenitrile trifluoroacetate Ex516 700 CH₂CN

512 3-{3-[(1,1-dioxidothiomorpholin- 4-yl)sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 649 701CH₂CN

505 3-{3-[(4-acetylpiperazin-1-yl)- sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 649 702CH₂CN

470 3-{3-[(pyridin-4-ylmethyl)- sulfonyl]phenyl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]propanenitrile Ex 516 703CH₂C≡CH H 314 4-[1-(1-phenylbut-3-yn-1-yl)-1H- Ex 705pyrazol-4-yl]-7H-pyrrolo[2,3-d]- pyrimidine trifluoroacetate 704 CH₂C≡CH

463 4-(1-{1-[3-(morpholin-4-yl- sulfonyl)phenyl]but-3-yn-1-yl}-1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidine Ex 705 705 CH₂C≡CH CN 3393-{1-[4-(7H-pyrrolo[2,3-d]- Ex 705 pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-yn-1-yl}benzonitrile trifluoroacetate 706 CH₂C≡CH CH═O 3423-{1-[4-(7H-pyrrolo[2,3-d]- Ex 706 pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-yn-1-yl}benzaldehyde trifluoroacetate 707 CH₂CO₂CH₃ CN 373methyl 3-(3-cyanophenyl)-3-[4- Ex 712 (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate trifluoroacetate 708 CH₂C≡CH

421 N,N-dimethyl-3-{1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-yn-1-yl}- benzenesulfonamide trifluoroacetate Ex705 709 CH₂CN

513 3-{2-cyano-1-[4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}-N-[4- (dimethylamino)phenyl]- benzenesulfonamide Ex649 710 CH₂CH₂—OCH₃

441 3-{3-methoxy-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-N,N- dimethylbenzenesulfonamide trifluoroacetate Ex712 711 CH₂C≡CH

433 N-phenyl-3-{1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-yn-1-yl}- benzamide trifluoroacetate Ex 705 712CH₂CH₂—OCH₃ H 334 4-[1-(3-methoxy-1-phenyl- Ex 712propyl)-1H-pyrazol-4-yl]-7H- pyrrolo[2,3-d]pyrimidine trifluoroacetate713 CH₂C≡CH

476 N-[4-(dimethylamino)phenyl]-3- {1-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1- yl]but-3-yn-1-yl}benzamidetrifluoroacetate Ex 705 714 CH₂CH₂OH

427 3-{3-hydroxy-1-[4-(7H-pyrrolo- [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl]-N,N- dimethylbenzenesulfonamide trifluoroacetate Ex712 715 CH₂—CH═CH₂ CN 341 3-{1-[4-(7H-pyrrolo[2,3-d]- Ex 715pyrimidin-4-yl)-1H-pyrazol-1- yl]but-3-en-1-yl]benzonitriletrifluoroacetate 716 CH₂—CH═CH₂ Br 394, 4-{1-[1-(3-bromophenyl)but-3- Ex716 396 en-1-yl]-1H-pyrazol-4-yl}-7H- pyrrolo[2,3-d]pyrimidinetrifluoroacetate 717 CH₂CH═CF₂ CN 377 3-{4,4-difluoro-1-[4-(7H- Ex 717pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol-1-yl]but-3-en-1-yl}-benzonitrile 718 CH₂CH═CF₂

501 4-(1-{4,4-difluoro-1-[3- (morpholin-4-ylsulfonyl)-phenyl]but-3-en-1-yl]-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]- pyrimidinetrifluoroacetate Ex 717 719 CH₂CH═CF₂

444 4-(1-{1-[3-(ethylsulfonyl)- phenyl]-4,4-difluorobut-3-en-1-yl}-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidine trifluoroacetate Ex717 720 CH₂CH═CF₂

458 4-(1-{1-[3-(benzyloxy)phenyl]- 4,4-difluorobut-3-en-1-yl}-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]- pyrimidine trifluoroacetate Ex 717 721CH₂OCH₃ H 320 4-[1-(2-methoxy-1-phenylethyl)- Ex 7121H-pyrazol-4-yl]-7H-pyrrolo- [2,3-d]pyrimidine 722 CH₂CH═CF₂

430 4-(1-{4,4-difluoro-1-[3-(methyl- sulfonyl)phenyl]but-3-en-1-yl}-1H-pyrazol-4-yl)-7H-pyrrolo- [2,3-d]pyrimidine trifluoroacetate Ex 717723 H CN 301 3-{[4-(7H-pyrrolo[2,3-d]- Ex 250pyrimidin-4-yl)-1H-pyrazol-1- yl]methyl}benzonitrile 724 CH₂CH₂CH₃ CN343 3-{1-[4-(7H-pyrrolo[2,3-d]- Ex 250 pyrimidin-4-yl)-1H-pyrazol-1-yl]butyl}benzonitrile 725 CH₂CH₂CHF₂

446 4-(1-{1-[3-(ethylsulfonyl)- phenyl]-4,4-difluorobutyl}-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]- pyrimidine trifluoroacetate Ex 717 726CH₂CH═CF₂

474 4-[1-(4,4-difluoro-1-{3-[(2- methoxyethyl)sulfonyl]phenyl}-but-3-en-1-yl)-1H-pyrazol-4-yl]- 7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate Ex 717

Example 649:3-[3-(Morpholin-4-ylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

Step 1: 4-[(3-Bromophenyl)sulfonyl]morpholine

Morpholine (0.19 mL, 0.0022 mol) in 1.0 ml of THF was added dropwise toa solution of 3-bromobenzenesulfonyl chloride (0.3 mL, 0.002 mol) andTEA (0.30 mL, 0.0022 mol) in dry 4.0 mL of THF cooled in an ice bath.The reaction mixture was stirred overnight at room temperature and wasthen partitioned between 0.05N HCl and ethyl acetate. The organic layerwas washed with water (2×), and brine (1×), and was then dried overanhydrous magnesium sulfate, filtered and then was concentrated in vacuoto give 4-[(3-bromophenyl)sulfonyl]morpholine as a white crystallineproduct (470 mg, 78%). LCMS (M+H)⁺: m/z=306, 308.

Step 2: (2E&Z)-3-[3-(Morpholin-4-ylsulfonyl)phenyl]acrylonitrile

The 4-[(3-bromophenyl)sulfonyl]morpholine (0.250 g, 0.000816 mol) wasdissolved in dry DMF (2.5 mL, 0.032 mol) and the mixture was degassedusing a stream of nitrogen. To this mixture was added TEA (0.23 mL,0.0016 mol), 2-propenenitrile (0.11 mL, 0.0016 mol), palladium acetate(0.011 g, 0.000049 mol), and triphenylphosphine (0.0364 g, 0.000139 mol)and again the mixture was degassed with nitrogen. The reaction mixturein a sealed tube was heated at 110° C. for 16 hours. The reactionmixture, after cooling to room temperature, was partitioned between0.05N HCl and ethyl acetate. The organic layer was washed with water(2×), and brine (1×), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo, to give(2E&Z)-3-[3-(morpholin-4-yl-sulfonyl)phenyl]acrylonitrile as an oil(0.240 gm, 85%) which was a mixture of cis and trans isomers. LCMS(M+H)⁺: m/z=279.

Step 3: 3-[3-(Morpholin-4-ylsulfonyl)phenyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

To a mixture of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(0.100 g, 0.000317 mol) and(2E&Z)-3-[3-(morpholin-4-ylsulfonyl)phenyl]acrylonitrile (0.097 g,0.00035 mol) in dry ACN (2.0 mL, 0.038 mol) was added DBU (0.095 mL,0.00063 mol), and the resulting mixture was stirred at room temperatureovernight. The reaction mixture was then diluted with water andextracted with ethyl acetate. The combined organic phase was washed withwater (2×), and brine (1×), dried over magnesium sulfate, filtered andthen concentrated in vacuo to give the crude product. The crude productwas purified by silica gel flash column chromatography using ethylacetate-hexanes (6:4) as an eluent to give3-[3-(morpholin-4-ylsulfonyl)phenyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrileas a viscous oil (62 mg, 32.94%). LCMS (M+H)⁺: m/z=594

Step 4

Using a procedure analogous to Example 61 for the removal of the SEMprotecting the title compound was isolated as an amorphous white solid(30 mg, 63.84%. LCMS (M+H)⁺: m/z=464. ¹H NMR (400 MHz, DMSO-d6): δ□ 8.88(s), 8.62 (s), 8.1 (s), 7.78 (m), 7.70 (m), 7.58 (m), 6.95 (m), 6.20(m), 3.84 (m), 3.70 (m), 3.45 (m), 2.78 (m).

Example 679:cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylacetonitrile

Step 1: 4-(Hydroxymethyl)cyclohexanol

Ethyl 4-oxocyclohexanecarboxylate (2.0 g, 0.012 mol) was dissolved inether (20.0 mL) and was then cooled at 0° C. Into the mixture was added1 M lithium tetrahydroaluminate in ether (20 mL) and the resultingmixture was stirred at 0° C. for 2 hours. The reaction was quenched withwater (2 mL) and 1 N NaOH (2 mL) and ether was added (100 mL). Theprecipitated solids were filtered off and the residue was used in thenext reaction. ¹H NMR (CDCl₃): δ 4.02 and 3.75 (m, 1H), 3.45-3.61 (m,2H), 2.02 (m, 2H), 1.84 (m, 1H), 1.52-1.80 (m, 2H), 1.44 (m, 1H), 1.32(m, 2H), 1.03 (m, 1H).

Step 2: 4-[(Trityloxy)methyl]cyclohexanol

4-(Hydroxymethyl)cyclohexanol (2.0 g, 0.015 mol) was dissolved inpyridine (15.0 mL) and the mixture was cooled to 0° C. To the reactionwas added triphenylmethyl chloride (4.7 g, 0.017 mol) and the resultingmixture was stirred at 0° C. for 2 hours and at 25° C. for 16 hours. Thereaction was then concentrated using a rotory evaporator, and theconcentrate was extracted with ethyl acetate. The organic extracts werewashed with water, saturated NaCl, dried (MgSO₄) and then concentratedin vacuo. The reaction was chromatographed on silica gel using 30%EtOAc/hexanes to give the cis isomer (0.74 g)¹H NMR (CDCl₃): □δ 7.52 (m,6H), 7.27 (m, 9H), 3.98 (m, 1H), 2.93 (m, 2H), 1.21-1.68 (m, 9H); andthe trans isomer (2.72 g)¹H NMR (CDCl₃): □δ 7.44 (m, 6H), 7.20-7.31 (m,9H), 3.54 (m, 1H), 2.88 (m, 2H), 1.98 (m, 2H), 1.88 (m, 2H), 1.60 (m,1H), 0.99-1.37 (m, 4H).

Step 3: trans-4-[(Trityloxy)methyl]cyclohexyl methanesulfonate

trans-4-[(Trityloxy)methyl]cyclohexanol (2.72 g, 0.00730 mol) wasdissolved in chloroform (30.0 mL) and the mixture was cooled at 0° C. Tothis mixture was added TEA (1.4 mL, 0.010 mol) and methanesulfonylchloride (0.68 mL, 0.0088 mol) and the resulting mixture was stirred at0° C. for 2 hours The reaction was then extracted with ethyl acetate andthe organic extracts were washed with water, saturated NaCl, dried(MgSO₄) and the concentrated in vacuo. 1H NMR (CDCl₃): □δ 7.43 (m, 6H),7.20-7.31 (m, 9H), 4.57 (m, 1H), 3.00 (m, 3H), 2.90 (m, 2H), 2.16 (m,2H), 1.93 (m, 2H), 1.09-1.60 (m, 5H).

Step 4:7-[2-(Trimethylsilyl)ethoxy]methyl-4-(1-cis-4-[(trityloxy)methyl]cyclohexyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

4-(1H-Pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(1.5 g, 0.0048 mol) was mixed with sodium hydride (0.34 g, 0.0086 mol)and trans-4-[(trityloxy)methyl]cyclohexyl methanesulfonate (3.00 g,0.00666 mol) and the mixture was cooled to −78° C. To this mixture wasadded DMF (8.3 mL) and the mixture was allowed to warm to 25° C. and wasstirred for 20 minutes. The warmed mixture was stirred at 55° C. for 48hours. The reaction was extracted with ethyl acetate and the organicextracts were washed with water, saturated NaCl, dried (MgSO₄) and thenconcentrated in vacuo. The concentrate was chromatographed on silica gelusing 40% EtOAc/hexanes to give the product. LC/MS (M+H)⁺: 670, ¹H NMR(CDCl₃): □δ 8.89 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 6.84-7.51 (m,10H), 6.87 (d, 1H), 5.73 (s, 2H), 4.39 (m, 1H), 3.60 (m, 2H), 3.12 (m,2H), 1.76-2.11 (m, 9H), 0.96 (m, 2H), 0.00 (s, 9H).

Step 5:cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethanol

7-[2-(Trimethylsilyl)ethoxy]methyl-4-(1-cis-4-[(trityloxy)methyl]cyclohexyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine(0.3 g, 0.0004 mol) was dissolved in methanol (7.0 mL) and THF (2.0 mL,0.025 mol) and 4.0 M HCl in 1,4-dioxane (0.5 mL) was added. The reactionwas then stirred at 25° C. for 2 hours TLC analysis showed no startingmaterial present and LCMS analysis showed the presence of the product.The reaction was added to a saturated NaHCO₃ solution and was extractedwith ethyl acetate. The organic extracts were washed with water,saturated NaCl, dried (MgSO₄) and concentrated in vacuo. The concentratewas chromatographed on silica gel using EtOAc as eluent to give theproduct. LC/MS (M+H)⁺: 428

¹H NMR (CDCl₃): □δ 8.89 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.44 (d,1H), 6.87 (d, 1H), 5.73 (d, 2H), 4.41 (m, 1H), 3.51-3.71 (m, 4H), 2.31(m, 2H), 2.08 (m, 3H), 1.70-1.93 (m, 4H), 0.98 (m, 2H), 0.00 (s, 9H).

Step 6:cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethylmethanesulfonate

cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethanolwas dissolved in chloroform (3.00 mL) and was cooled to 0° C. To thereaction was added TEA (0.10 mL, 0.00072 mol) and methanesulfonylchloride (0.05 mL, 0.0006 mol) and this mixture was stirred at 0° C. for2 hours at which time LCMS analysis showed mainly the product present inthe mixture. The reaction was extracted with ethyl acetate and theorganic extracts were washed with water, saturated NaCl, dried (MgSO4)and concentrated in vacuo. LC/MS (M+H)⁺: 506

Step 7:cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylacetonitrile

cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethylmethanesulfonate (0.10 g, 0.00020 mol) and sodium cyanide (0.050 g,0.0010 mol) and DMSO (1.0 mL) were mixed. The mixture was stirred at 60°C. for 24 hours, at which time LCMS analysis showed most of the startingmaterial had been consumed. The reaction was extracted with ethylacetate and the organic extracts were washed with water, saturated NaCl,dried (MgSO₄) and concentrated in vacuo. The concentrate waschromatographed on silica gel using EtOAc as eluent to give the product.LC/MS (M+H)⁺: 437, ¹H NMR (CDCl₃): □δ 8.90 (s, 1H), 8.36 (s, 1H), 8.31(s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.43 (m, 1H), 3.60(m, 2H), 2.45 (d, 2H, J=7.6 Hz), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93(m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).

Step 8:cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylacetonitrile

cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylacetonitrile(0.080 g, 0.00018 mol) and TFA (0.50 mL, 0.0065 mol) were added to DCM(3.00 mL, 0.0468 mol) and the mixture was stirred at 25° C. for 16hours. The reaction was concentrated by roto-evaporation and theconcentrate was dissolved in methanol (3.0 mL, 0.074 mol) and ammoniumhydroxide (0.5 mL, 0.01 mol) was added This reaction was stirred at 25°C. for 6 hours at which time LCMS analysis showed no starting materialpresent. The reaction was chromatographed on silica gel using 5%MeOH/EtOAc to give the product.

LC/MS (M+H)⁺:307, ¹H NMR (CD₃OD): □δ 8.64 (s, 1H), 8.55 (s, 1H), 8.31(s, 1H), 7.50 (d, 1H), 6.96 (d, 1H), 4.42 (m, 1H), 2.61 (d, 2H, J=8.0Hz), 2.27 (m, 2H), 1.70-2.15 (m, 7H).

Example 680:cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethylthiocyanate

Step 1:cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethylthiocyanate

cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethylmethanesulfonate (0.10 g, 0.00020 mol) was dissolved in DMSO (1.00 mL)with potassium thiocyanate (0.082 g, 0.00084 mol). The reaction washeated at 68° C. for 4 days at which time LCMS analysis showed −4:1product/starting material ratio. The reaction was extracted with ethylacetate and the organic extracts were washed with water, saturated NaCl,dried (MgSO₄) and concentrated in vacuo. The concentrate waschromatographed on silica gel using 1:1 EtOAc/hexanes to give theproduct. LC/MS (M+H)⁺: 469, ¹H NMR (CDCl₃): □δ 8.89 (s, 1H), 8.36 (s,1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (m,1H), 3.60 (m, 2H), 3.05 (m, 2H), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93(m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).

Step 2:cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethylthiocyanate)

cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethylthiocyanate was dissolved in methanol (2.0 mL, 0.049 mol) and DCM (2.0mL, 0.031 mol), and TFA (0.5 mL, 0.006 mol) was added. The resultingmixture was stirred at 25° C. for 16 hours. TLC analysis showed nostarting material present and LCMS analysis showed product. The reactionwas concentrated using a rotary evaporator and the concentrate waschromatographed on silica gel using 2% MeOH/EtOAc to give the product.LC/MS (M+H)⁺:339, ¹H NMR (CD₃OD) δ 8.65 (s, 1H), 8.55 (s, 1H), 8.31 (s,1H), 7.50 (d, 1H), 6.96 (d, 1H), 4.43 (m, 1H), 3.20 (d, 2H, J=7.6 Hz),2.24 (m, 2H), 1.80-2.17 (m, 7H).

Example 681:N-5-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexyl-methyl)thio]-4H-1,2,4-triazol-3-ylpyrimidin-2-aminetrifluoroacetate

Step 1:5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-amine

cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethylmethanesulfonate (124.56 mg, 0.00024 mol), and5-amino-4H-1,2,4-triazole-3-thiol (43.00 mg, 0.0003702 mol) weredissolved in DMF (1.20 mL) and potassium carbonate (0.122 g, 0.000887mol) was added. The reaction was stirred at 50° C. for 18 h, at whichtime LCMS showed nearly complete reaction, and product present. Thereaction was extracted with ethyl acetate and the organic extracts werewashed with water, saturated NaCl, dried (MgSO₄) and concentrated invacuo. The concentrate was chromatographed on silica gel using EtOAc aseluent to give the product.

LC/MS (M+H)⁺: 526, ¹H NMR (CDCl₃): □δ 8.90 (s, 1H), 8.40 (s, 1H), 8.30(s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (brs, 2H), 4.41(m, 1H), 3.60 (m, 2H), 3.22 (d, 2H, J=7.2 Hz), 2.29 (m, 2H), 1.70-2. 10(m, 7H), 0.98 (m, 2H), 0.00 (s, 9H).

Step 2:5-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-amine

5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-amine(9a) was dissolved in TFA (1 mL) and was stirred for 2 h. The solutionwas concentrated using a rotary evaporator to remove TFA. The residuewas dissolved in methanol (1 mL) and ammonium hydroxide (1 mL) added.The solution was stirred overnight. LCMS showed complete de-protection.The solution was concentrated using a rotary evaporator. The product wasisolated by prep LCMS using a 30 mm×100 mm C18 column; 11% CH₃CN—H₂O(0.1% TFA), 1.5 min, to 33% at 6 min; 60 mL/min; detector set at m/z396; retention time, 5.5 min (2 runs). The eluate was freeze dried.Yield 21 mg (di-TFA salt). LC/MS (M+H)⁺:396, ¹H NMR (d₆-DMSO) δ 12.9 (brs, 1H, NH); 8.9 (2 singlets, 2H); 8.5 (s, 1H); 7.9 (m, 1H); 7.3 (m, 1H);4.4 (m, 1H, NCH); 3.1 (d, 2H); 2.2 (m, 2H); 1.9 (m, 3H); 1.7 (m, 2H);1.6 (m, 2H). MS(ES) 396 (M+1).

Example 682:N-5-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexyl-methyl)thio]-4H-1,2,4-triazol-3-ylpyrimidin-2-aminetrifluoroacetate

Step 1:N-5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-ylpyrimidin-2-amine

In a vial [A]5-[(cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-amine(0.047 g, 0.000089 mol) was heated with 2-chloropyrimidine (0.011 g,0.000096 mol) in 1,4-dioxane (1.00 mL, 0.0128 mol) at 150° C. for 40minutes in a microwave reactor. LCMS analysis showed that no reactionhad taken place. To the reaction was added 2-chloropyrimidine (0.020 g,0.00017 mol) with cesium carbonate (0.033 g, 0.00010 mol) and copper(I)iodide (4.00 mg, 0.0000210 mol) and this mixture was heated at 115° C.for 3 hours, at which time LCMS analysis showed no starting materialpresent and mainly product was present. The reaction was chromatographedon silica gel using 2% MeOH/EtOAc to give the product. LC/MS (M+1)⁺:604,¹NMR(CDCl₃): 8.89 (s, 1H), 8.82 m, 2H), 8.43 (s, 1H), 8.30 (s, 1H), 7.44(d, 1H), 7.23 (m, 1H), 7.03 (br s, 2H), 6.88 (d, 1H), 5.73 (s, 2H), 4.40(m, 1H), 3.60 (m, 2H), 3.35 (d, 2H), 2.34 (m, 2H), 1.80-2.15 (m, 7H),0.98 (m, 2H), 0.00 (s, 9H).

Step 2:N-5-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-ylpyrimidin-2-amine

N-5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-ylpyrimidin-2-amine(0.024 g, 0.000040 mol) was dissolved in DCM (4.00 mL), and TFA (0.50mL, 0.0065 mol) was added. The reaction was stirred at 25° C. for 16hours and was concentrated in vacuo. The residue was dissolved inmethanol (3.00 mL) and concentrated ammonium hydroxide (0.50 mL) wasadded. This reaction was stirred at 25° C. for 2 hours at which timeLCMS analysis showed mostly product. The reaction was concentrated usinga rotary evaporator and the concentrate was purified by prep LC to givethe product as the trifluoroacetate salt. LC/MS (M+H)⁺:474, ¹H NMR(CD₃OD) δ 8.87 (s, 1H), 8.85 (s, 1H), 8.81 (s, 1H), 8.79 (s, 1H), 8.45(s, 1H), 7.85 (d, 1H), 7.34 (m, 2H), 4.43 (m, 1H), 3.20 (d, 2H, J=7.6Hz), 2.24 (m, 2H), 1.80-2.17 (m, 7H).

Example 683:3-cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylpropanenitriletrifluoroacetate

Step 1: 2-(1,4-Dioxaspiro[4.5]dec-8-yl)ethanol

Ethyl 1,4-dioxaspiro[4.5]dec-8-ylacetate (3.40 g, 0.0149 mol) preparedaccording to the procedure of Itagaki, Noriaki; Kimura, Mari; Sugahara,Tsutomu; Iwabuchi, Yoshiharu. (Organic Letters 2005; 7(19); 4181-4183.)was dissolved in ether (30.00 mL) and the mixture was cooled to 0° C. Tothe reaction was added 1.00 M lithium tetrahydroaluminate in ether (15.0mL) and the resulting mixture was stirred at 0° C. for 60 minutes and at25° C. for 2 hours. The reaction was cooled and water (0.40 mL, 0.022mol) was added, followed by 1.00 M sodium hydroxide (0.40 mL). To thereaction was then added ether (100.00 mL) and the solid thatprecipitated was filtered off. The filtrate was concentrated using arotary evaporator to give the product. ¹H NMR (CDCl₃): 3.94 (s, 4H),3.67 (t, 2H), 1.20-1.80 (m, 11H).

Step 2: 4-(2-Hydroxyethyl)cyclohexanone

2-(1,4-Dioxaspiro[4.5]dec-8-yl)ethanol (2.70 g, 0.0145 mol) wasdissolved in acetone (10.00 mL) and THF (10.00 mL) and 6.00 M HCl (6.00mL) was added. The reaction was stirred at 25° C. for 16 hours,neutralized with NaHCO₃ solution and was then extracted with ethylacetate. The organic extracts were washed with water, and with saturatedNaCl, then dried (MgSO₄) and concentrated in vacuo. The crude productwas used in the next reaction without further purification.

¹H NMR (CDCl₃): 3.75 (m, 2H), 2.36 (m, 4H), 1.20-2.13 (m, 7H).

Step 3: 4-(2-Hydroxyethyl)cyclohexanol

4-(2-Hydroxyethyl)cyclohexanone (2.00 g, 0.0141 mol) was dissolved inether (30.00 mL) and was cooled at 0° C. To the reaction was added 1.0 Mlithium tetrahydroaluminate in ether (14.1 mL) and the resulting mixturewas stirred at 0° C. for 2 hours and at 25° C. for 16 hours. To thereaction was added THF (20.00 mL) and this mixture was cooled at 0° C.and then water (0.40 mL, 0.022 mol) was added, followed by 1.00 M sodiumhydroxide (0.40 mL). To the reaction was then added ether (100.00 mL)and the resulting mixture was stirred for 10 minutes, then was filteredand the filtrate was concentrated using a rotary evaporator to providethe crude product. The crude product was used in the next reactionwithout further purification.

¹H NMR (CDCl₃): 3.96 and 3.57 (m, 1H) minor and major CHOH (˜1:5 ratio)3.70 (m, 2H), 0.94-2.02 (m, 11H).

Step 4: 4-[2-(Trityloxy)ethyl]cyclohexanol

4-(2-Hydroxyethyl)cyclohexanol (crude from the previous reaction) (1.88g, 0.0130 mol) was dissolved in pyridine (20.00 mL) and was cooled at 0°C. To the reaction was added triphenylmethyl chloride (4.0 g, 0.014 mol)and this mixture was stirred at 0° C. for 2 hours and at 25° C. for 16hours.

The reaction was concentrated using a rotary evaporator and theconcentrate was extracted with ethyl acetate. The organic extracts werewashed with water, and saturated NaCl, then dried (MgSO₄) andconcentrated in vacuo. The concentrate was chromatographed on silica gel(30% EtOAc/hexanes) to give the trans isomer (1.98 g)

¹H NMR (CDCl₃): 7.42-7.45 (m, 6H), 7.20-7.30 (m, 9H), 3.50 (m, 1H), 3.07(m, 2H), 1.93 (m, 2H), 1.66 (m, 2H), 1.17-1.60 (m, 5H), 0.89 (m, 2H).

Step 5: trans-4-[2-(Trityloxy)ethyl]cyclohexyl methanesulfonate

trans-4-[2-(Trityloxy)ethyl]cyclohexanol (1.95 g, 0.00504 mol) wasdissolved in chloroform (40.00 mL) and the mixture was cooled to 0° C.To the reaction was added TEA (0.98 mL, 0.0071 mol) and methanesulfonylchloride (0.47 mL, 0.0060 mol) and this mixture was stirred at 0° C. for2 hours The reaction was then extracted with ethyl acetate and theorganic extracts were washed with water, and saturated NaCl, then dried(MgSO₄) and concentrated in vacuo.

¹H NMR (CDCl₃): 7.41-7.45 (m, 6H), 7.20-7.32 (m, 9H), 4.55 (m, 1H), 3.07(m, 2H), 2.10 (m, 2H), 1.70 (m, 2H), 1.20-1.60 (m, 5H), 0.95 (m, 2H).

Step 6:7-[2-(Trimethylsilyl)ethoxy]methyl-4-(1-cis-4-[2-(trityloxy)ethyl]cyclohexyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

4-(1H-Pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(1.0 g, 0.0032 mol) was mixed with sodium hydride (0.23 g, 0.0058 mol)and trans-4-[2-(trityloxy)ethyl]cyclohexyl methanesulfonate (2.10 g,0.00452 mol) and this mixture was cooled to −78° C. To the reaction wasadded DMF (6.00 mL) and this mixture was allowed to warm to 25° C. andwas then stirred for 20 minutes. The reaction was stirred at 55° C. for48 hours at which time LCMS analysis showed mostly product. The reactionwas extracted with ethyl acetate and the organic extracts were washedwith water and saturated NaCl, then dried (MgSO₄) and concentrated invacuo. The concentrate was chromatographed on silica gel using 40%EtOAc/hexanes to give the product.

LC/MS (M+H)⁺:684, ¹H NMR (CDCl₃): 8.89 (s, 1H), 8.35 (br s, 1H), 8.30(s, 1H), 7.50 (m, 6H), 7.44 (d, 1H), 7.27-7.32 (m, 9H), 6.87 (d, 1H),5.73 (s, 2H), 4.33 (m, 1H), 3.60 (m, 2H), 3.17 (t, 2H), 1.50-2.25 (m,11H). 0.98 (m, 2H), 0.00 (s, 9H).

Step 7:2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylethanol(7b)

7-[2-(Trimethylsilyl)ethoxy]methyl-4-(1-cis-4-[2-(trityloxy)ethyl]cyclohexyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine(1.45 g, 0.00212 mol) was dissolved in methanol (30.00 mL) and THF(10.00 mL) and 4.0 M HCl in 1,4-dioxane (2.00 mL) was added. The mixturewas stirred at 25° C. for 2 hours, at which time, TLC analysis showed nostarting material present and LCMS analysis showed the presence of theproduct. The reaction was added into a saturated NaHCO₃ solution, andwas then extracted with ethyl acetate. The organic extracts were washedwith water and saturated NaCl, then dried (MgSO₄) and concentrated invacuo. The concentrate was chromatographed on silica gel using EtOAc aseluent to give the product. LC/MS (M+H)⁺: 442

Step 8:2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylethylmethanesulfonate (8b)

2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylethanol(0.89 g, 0.0020 mol) was dissolved in DCM (12.00 mL, 0.1872 mol) and wascooled at 0° C. To the reaction was added TEA (0.43 mL, 0.0031 mol) andmethanesulfonyl chloride (0.19 mL, 0.0024 mol) and this mixture wasstirred at 0° C. for 2 hours at which time LCMS analysis showed mainlyproduct present. The reaction was extracted with ethyl acetate and theorganic extracts were washed with water and saturated NaCl, then dried(MgSO₄) and concentrated in vacuo. LC/MS (M+H)⁺:520, ¹H NMR (CDCl₃):8.90 (s, 1H), 8.38 (br s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.88 (d, 1H),5.73 (s, 2H), 4.40 (m, 1H), 4.27 (t, 2H), 3.60 (m, 2H), 3.07 (s, 3H),1.60-2.40 (m, 11H). 0.98 (m, 2H), 0.00 (s, 9H)

Step 9:3-cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylpropanenitriletrifluoroacetate (9b)

2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylethylmethanesulfonate (0.075 g, 0.00014 mol) was dissolved in DMSO (1.50 mL)and sodium cyanide (0.035 g, 0.00072 mol) was added. The reaction wasstirred at 40° C. for 16 hours at which time LCMS analysis showed nostarting material present. The reaction was then extracted with ethylacetate and the organic extracts were washed with water and saturatedNaCl, then dried (MgSO₄) and concentrated in vacuo. The residue wasdissolved in DCM (3.00 mL) and TFA (0.50 mL, 0.0065 mol) was added. Thismixture was stirred at 25° C. for 16 hours at which time LCMS analysisshowed mostly the hydroxymethyl intermediate. The mixture wasconcentrated using a rotary evaporator and the concentrate was dissolvedin methanol (3.00 mL) and concentrated ammonium hydroxide (0.50 mL) wasadded. The reaction was stirred at 25° C. for 3 hours at which time LCMSanalysis showed no starting material present. The reaction was thenconcentrated using a rotary evaporator and the concentrate was purifiedby prep LC to give the product as the TFA salt (47.8 mg). LC/MS(M+H)⁺:321, ¹H NMR (CD₃OD): 8.86 (s, 1H), 8.81 (s, 1H), 8.44 (s, 1H),7.84 (d, 1H), 7.31 (d, 1H), 4.48 (m, 1H), 2.51 (m, 2H), 2.28 (m, 2H),2.00 (m, 2H), 1.80 (m, 5H), 1.67 (m, 2H).

Example 684:5-[(2-cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexyl-ethyl)thio]-4H-1,2,4-triazol-3-aminetrifluoroacetate

2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylethylmethanesulfonate (0.060 g, 0.00012 mol) was dissolved in DMF (1.31 mL)with 5-amino-4H-1,2,4-triazole-3-thiol (0.020 g, 0.00017 mol) andpotassium carbonate (0.024 g, 0.00017 mol). This mixture was heated at40° C. for 18 hours at which time LCMS analysis showed no startingmaterial present. The reaction was diluted with EtOAc, filtered and wasthen concentrated using a rotary evaporator. The residue was dissolvedin DCM (3.60 mL) and TFA (0.60 mL, 0.0078 mol) was added. This mixturewas stirred at 25° C. for 5 hours and was then concentrated using arotary evaporator. The residue was dissolved in methanol (3.60 mL) andconcentrated ammonium hydroxide (0.60 mL) was added and this mixture wasstirred at 25° C. for 2 hours. The reaction was concentrated using arotary evaporator and the concentrate was purified by prep. LC to givethe product. LC/MS (M+H)⁺:410, ¹H NMR (CD₃OD): 8.85 (s, 1H), 8.80 (s,1H), 8.44 (s, 1H), 7.83 (d, 1H), 7.30 (d, 1H), 4.46 (m, 1H), 3.17 (m,2H), 2.27 (m, 2H), 2.00 (m, 2H), 1.62-1.90 (m, 7H).

Example 685:4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitriletrifluoroacetate

Step 1: 1,4-Dioxaspiro[4.5]decan-8-ol

1,4-Dioxa-spiro[4.5]decan-8-one (2.00 g, 0.0128 mol) was dissolved inether (50 mL) and the mixture was cooled to 0° C. To the reaction wasadded 1 M lithium tetrahydroaluminate in ether (7.0 mL) and this mixturewas stirred at 0° C. for 2 hours at which time TLC analysis showed nostarting material present. The reaction was then quenched with water and1 N NaOH (0.5 mL of each) and then filtered. The filtered solid waswashed with ether and the combined ether filtrate was concentrated usinga rotary evaporator to give the product. NMR (CDCl₃): 3.94 (m, 4H), 3.81(m, 1H), 1.79-1.92 (m, 4H), 1.54-1.70 (m, 4H).

Step 2: 1,4-Dioxaspiro[4.5]dec-8-yl methanesulfonate

1,4-Dioxaspiro[4.5]decan-8-ol (0.40 g, 0.0025 mol) was dissolved inchloroform (10.0 mL) and the resulting mixture was cooled at 0° C. Tothe mixture was added TEA (0.49 mL, 0.0035 mol) and methanesulfonylchloride (0.23 mL, 0.0030 mol) and this mixture was stirred at 0° C. for2 hours. The reaction was extracted with ethyl acetate and the organicextracts were washed with water, and saturated NaCl, then dried (MgSO₄)and concentrated in vacuo. The crude product was used in the nextreaction without further purification.

¹H NMR (CDCl₃): 4.85 (m, 1H), 3.95 (m, 4H), 3.02 (s, 3H), 1.98-2.05 (m,4H), 1.82-1.89 (m, 2H), 1.61-1.70 (m, 2H).

Step 3:4-[1-(1,4-Dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

A mixture of 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (0.50 g,0.0015 mol) with4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(0.36 g, 0.0011 mol) and sodium hydride (0.082 g, 0.0020 mol) was cooledat −78° C. and DMF (2.0 mL) was added. The reaction was allowed to warmto 25° C. and was then stirred for 20 minutes and was then heated to 55°C. for 24 hours. The reaction was then extracted with ethyl acetate. Theorganic extracts were washed with water and saturated NaCl, then dried(MgSO₄) and concentrated in vacuo. The concentrate was chromatographedon silica gel using 1:1 EtOAc/hexanes to give the product. LC/MS(M+H)⁺:456, ¹H NMR (CDCl₃): 8.89 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H),7.44 (d, 1H), 6.87 (d, 1H), 5.73 (s, 2H), 4.38 (m, 1H), 4.06 (s, 4H),3.60 (m, 2H), 2.22-2.31 (m, 4H), 2.00 (m, 2H), 1.86 (m, 2H), 0.98 (m,2H), 0.00 (s, 9H)

Step 4:4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanone

To4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(2.13 g, 0.00467 mol), was added acetone (85 mL) followed by 12 M HCl inwater (4.0 mL). The reaction was stirred at RT. After 1 h, LCMS analysisshowed 66% reaction. After 4 h, HPLC showed 80% reaction. After 20 h,HPLC showed no change (and no loss of SEM). The reaction mixture wasquenched into excess sat'd NaHCO₃. The acetone was removed byroto-evaporation. The resulting mixture of aqueous bicarbonate and awhite solid was then extracted with EtOAc. The combined organic extractwas shaken with sat'd NaCl, dried over Na₂SO₄, then concentrated todryness to leave 2.0 g of a crude product. TLC (5% iPrOH-40%EtOAc-hexane): product Rf 0.12 (ketal 0.22). The crude product waspurified by automatic flash chromatography on silica gel. Used a 40 gcolumn; flow 40 mL/min; [A=2% iPrOH-hexane] [B=6% iPrOH-50%EtOAc/hexane]; A, 2 min; Gradient to B in 25 min, then B for 10 min. Theeluent was concentrated using a rotary evaporator to give 1.3 g of awhite solid. HPLC Method: Zorbax SB C18, 5 m, 15 cm, 35° C., flow 1.2mL/min, 10% CH₃CN—H₂O (0.05% TFA), to 100% CH₃CN in 9.0 min; stop time12.3 min; detector 268 nm; retention time starting material, 7.4 min;product, 6.9 min (UV max 220, 268, 300, 322 nm). ¹H NMR (CDCl₃) δ 8.8(s, 1H); 8.3 (m, 2H); 7.4 (d, 1H); 7.3 (s, 1H); 6.8 (d, 1H); 5.7 (s,2H); 4.7 (m, 1H, NCH); 3.6 (t, 2H); 2.3-2.5 (m, 8H); 0.9 (t, 2H); −0.1(s, 9H). MS(ES) 412 (M+1).

Step 5:4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile

To a solution of 1.0 M potassium tert-butoxide in THF (1.90 mL) at 0° C.was added a solution of diethyl cyanomethylphosphonate (321 μL, 0.00198mol) in THF (4 mL) dropwise. The reaction was held for 10 min, then itwas added to a solution of4-[4-(7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanone(743 mg, 0.00180 mol) in THF (5 mL) stirring at 0° C. under a nitrogenatmosphere. The reaction was stirred 1.5 h at rt. LCMS analysis showedclean conversion to the desired product. To the reaction mixture wasthen added water and EtOAc. The phases were separated and the aqueousphase was extracted with EtOAc. The combined organic extract was washedwith water, then sat'd NaCl, then dried over Na₂SO₄, and concentrated todryness to yield 0.76 g of a white crystalline solid (TLC (EtOAc) Rf0.33). The product was purified by automatic flash chromatography onsilica gel. Used 40 g column; flow 40 mL/min; [A=hexane] [B=EtOAc]; A, 2min; Gradient to B in 20 min. Rotary evaporation yielded 0.70 g of awhite crystalline solid (89% yield). ¹H NMR (CDCl₃) δ 8.9 (s, 1H); 8.3(s, 2H); 7.4 (d, 1H); 7.3 (s, 1H); 6.9 (d, 1H); 5.7 (s, 2H); 5.3 (s, 1H,olefin); 4.5 (m, 1H, NCH); 3.6 (m, 2H); 3.2 (m, 1H); 2.7 (m, 1H); 2.5(m, 4H); 2.1 (m, 2H); 1.0 (m, 2H); −0.1 (s, 9H). MS(ES) 435 (M+1).

Step 6:4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile

A solution of TFA (0.5 mL, 0.006 mol) and4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile(22.7 mg, 0.0000522 mol), was stirred for 1.5 h. The solution was thenconcentrated using a rotary evaporator to remove TFA. LCMS analysisshowed conversion to the hydroxymethyl intermediate, M+H 335. Methanolwas added; and the methanol mixture was concentrated again using arotary evaporator. The resulting residue was dissolved in methanol (1mL) and ammonium hydroxide (0.25 mL, 0.0064 mol) was added. Theresulting solution was stirred for 16 h. LCMS analysis showed completede-protection. The solution was then concentrated using a rotaryevaporator. The product was isolated by prep HPLC using a 30 mm×100 mmC18 column; 18% CH₃CN—H₂O (0.1% TFA), 1 min, to 35% at 6 min; 60 mL/min;detector set at 254 nm; retention time, 4.4 min. The eluate was freezedried. yield 7.6 mg of a white solid (TFA salt; racemic; 34.6%). ¹H NMR(d₆DMSO) δ 12.9 (br s, 1H, NH); 8.9 (s, 2H); 8.5 (s, 1H); 7.8 (m, 1H);7.3 (m, 1H); 5.6 (s, 1H, olefin); 4.6 (m, 1H, NCH); 2.8 (m, 1H); 2.6 (m,1H); 2.5 (m, 2H); 2.3 (m, 2H) 2.0 (m, 2H). MS(ES) 305 (M+1).

Example 686:cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanecarbonitriletrifluoroacetate

Step 1:cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanecarbaldehydeoxime

A solution of sulfur trioxide-pyridine complex (53.4 mg, 0.000336 mol)in DMSO (0.3 mL, 0.004 mol) was added to a solution ofcis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethanol(57.4 mg, 0.000134 mol) and TEA (56.1 μL, 0.000403 mol) in DCM (0.3 mL,0.004 mol) at −10° C. The mixture was stirred vigorously at 10-20° C.for one hour. LCMS analysis showed conversion to the aldehyde. Themixture was then poured into ice-water, and extracted with DCM. Theextracts were washed with 10% citric acid, water, saturated aqueoussodium bicarbonate, water, and brine, and then dried over sodiumsulfate. Concentration gave 57 mg of a residue.

To the resulting residue was added hydroxylamine-HCl (50 mg), 1 mL 20%K₂CO₃, and 3 mL MeOH and this mixture was stirred at rt until LCMSshowed conversion to the corresponding oxime, M+H 441. The product wasisolated by prep HPLCMS using a 30 mm×10, 0 mm, C18 column; 30%CH₃CN—H₂O (0.1% TFA), 1 min, to 60% at 6 min; 60 mL/min; detector set atm/z 441; retention time, 6.0 min. freeze-dried. yield 17.4 mg of a whitesolid.

Step 2:cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanecarbonitrile

[A]cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanecarbaldehydeoxime (11.0 mg, 0.0000250 mol) was dissolved in pyridine (0.25 mL,0.0031 mol), and benzenesulfonyl chloride (10.0 μL, 0.0000784 mol) wasadded and the resulting mixture was stirred at rt. After stirring 15 h,LCMS analysis showed formation of the product, M+H 423. The product wasisolated by prep HPLCMS using a 19 mm×100 mm C18 column; 45% CH₃CN—H₂O(0.1% NH₄OH), 1 min, to 75% at 6 min; 30 mL/min; detector set at m/z423; retention time, 4.8 min. The eluent was concentrated using a rotaryevaporator to give 8 mg of the desired product.

The product was dissolved in TFA (0.25 mL). stirred for 2 h. Thesolution was concentrated using a rotary evaporator to remove TFA.Methanol was added and the mixture was concentrated again. LCMS showedclean conversion to the hydroxymethyl intermediate (M+H 323). Theresidue was dissolved in methanol (1 mL) and ammonium hydroxide (0.25mL) was added. The solution was stirred 0.5 h, at which time, LCMSshowed complete de-protection to the desired product M+H 293. Themixture was then concentrated by roto-evaporation, and the product wasisolated by prep HPLCMS using a 19 mm×100 mm C18 column; 15% CH₃CN—H₂O(0.1% TFA), 1.5 min, to 30% at 6 min; 30 mL/min; detector set at m/z293; retention time, 5.2 min. The eluate was freeze dried to yield 5.5mg of the product as a TFA salt. ¹H NMR (d₆-DMSO) δ 12.82 (br s, 1H,NH); 8.87 (s, 1H); 8.85 (s, 1H); 8.48 (s, 1H); 7.82 (m, 1H); 7.24 (m,1H); 4.40 (m, 1H, NCH); 3.22 (m, 1H); 2.05 (m, 6H); 1.79 (m, 2H). MS(ES)293 (M+1).

Example 687:2-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexyl-methyl)sulfinyl]benzonitriletrifluoroacetate

Step 1:4-[1-(cis-4-[(2-Bromophenyl)thio]methylcyclohexyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

This compound was prepared from(cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethylmethanesulfonate as in Example 686[A]. Yield 73%. The product waspurified using the following HPLC method: Zorbax SB C18, 5 m, 15 cm, 35C, flow 1.2 mL/min, 10% CH₃CN—H₂O (0.05% TFA), to 100% CH₃CN in 9.0 min;stop time 12.3 min; detector 254 nm; retention time starting mesylate,7.5 min; product, 9.9 min (UV max 215, 258, 300, & 326 nm). TLC: Rf 0.3using 35% EtOAc/5% iPrOH/hexane. The product was purified by automatedsilica gel flash chromatography using 30% EtOAc/5% iPrOH/hexane. ¹H NMR(CDCl₃) δ 8.84 (s, 1H); 8.31 (s, 1H); 8.26 (s, 1H); 7.55 (m, 1H); 7.39(d, 1H); 7.27 (m, 2H); 7.03 (m, 1H); 6.82 (d, 1H); 5.67 (s, 2H); 4.34(m, 1H, NCH); 3.55 (m, 2H); 2.98 (d, 2H); 2.28 (m, 2H); 2.02 (m, 3H);1.83 (m, 4H); 0.92 (m, 2H); −0.06 (s, 9H). MS(ES) 598/600 1:1 (M+1).

Step 2:2-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]benzonitrile

4-[1-(cis-4-[(2-Bromophenyl)thio]methylcyclohexyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(62.7 mg, 0.000105 mol), zinc cyanide (123 mg, 0.00105 mol), andtetrakis(triphenylphosphine)palladium(0) (30.2 mg, 0.0000262 mol) werestirred in DMF (3 mL) and the solution was flushed with nitrogen. Thesolution was then heated to 100° C. for 25 min in a microwave reactor.LCMS and HPLC analyses showed >90% reaction. The product was isolated byprep HPLCMS using a 30 mm×100 mm C18 column; 52% CH₃CN—H₂O (0.1% TFA),1.5 min, to 75% at 6 min; 60 mL/min; detector set at 545 nm. The eluentwas concentrated using a rotary evaporator to give 37 mg of the2-cyanophenylsulfide TFA salt. HPLC Method: Zorbax SB C18, 5 m, 15 cm,35 C, flow 1.2 mL/min, 10% CH₃CN—H₂O (0.05% TFA), to 100% CH₃CN in 9.0min; stop time 12.3 min; detector 265 nm; retention time startingmaterial, 9.9 min; product, 8.9 min. MS(ES) 545 (M+1).

Step 3:2-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)sulfinyl]-benzonitrile

A solution of2-[(cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]benzonitrile(30.6 mg, 0.0000562 mol), in TFA (1 mL) was stirred for 2 h. Thesolution was concentrated using a rotary evaporator to remove TFA.Methanol was added, and the mixture was concentrated again. Theresulting residue was dissolved in methanol (1 mL) and ammoniumhydroxide (1 mL) was added. The resulting solution was stirredovernight, at which time HPLC showed complete deprotection. The productwas isolated by prep HPLCMS using a 19 mm×100 mm C18 column; 30%CH₃CN—H₂O (0.1% TFA), 1.5 min, to 59% at 6 min; 30 mL/min; detector setat m/z 415 nm; retention time, 4.7 min. The eluate was concentratedusing a rotary evaporator to give 36 mg of the sulfide TFA salt, acolorless glassy material. NMR (d₆-DMSO) δ 12.82 (br s, 1H, NH); 8.84 (2singlets, 2H); 8.45 (s, 1H); 7.8 (m, 2H); 7.64 (m, 2H); 7.34 (td, 1H);7.24 (s, 1H); 4.39 (m, 1H, NCH); 3.23 (d, 2H); 2.19 (m, 2H); 1.89 (m,3H); 1.72 (m, 4H). MS(ES) 415 (M+1). This material was then dissolved inCH₂Cl₂ and cooled to 0° C. To the cooled mixture was added MCPBA(12.9mg, 0.0000562 mol), and the resulting mixture was stirred for 1 h. LCMSshowed conversion to the product, and no remaining sulfide. The reactionmixture was concentrated by rotovap, and the product was isolated byprep HPLCMS using a 19 mm×100 mm C18 column; 18% CH₃CN—H₂O (0.1% TFA),1.0 min, to 35% at 6 min; 30 mL/min; detector set at m/z 431 nm;retention time, 5.6 min. The product was isolated from the eluent byfreeze-drying. The yield was 27.6 mg of the TFA salt. The HPLC methodwas: Zorbax SB C18, 5 μm, 15 cm, 35° C., flow 1.2 mL/min, 10% CH₃CN—H₂O(0.05% TFA), to 100% CH₃CN in 9.0 min; stop time 12.3 min; detector 268nm; retention time starting material, 5.6 min; sulfoxide, 4.8 min;sulfone, 5.2 min; MCPBA, 6.0 min. ¹H NMR (CDCl₃) δ 12.1 (br s, 1H, NH);9.0 (s, 1H); 8.9 (s, 1H); 8.3 (s, 1H); 8.1 (m, 1H); 7.9 (m, 1H); 7.8 (m,1H); 7.6 (m, 2H); 7.0 (m, 1H); 4.4 (m, 1H, NCH); 3.1 (dd, 1H); 2.9 (dd,1H); 2.5 (m, 1H); 2.3 (m, 1H); 2.3-1.7 (m, 7H). MS(ES) 431 (M+1).

Example 688:2-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexyl-methyl)sulfonyl]benzonitriletrifluoroacetate

2-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)sulfinyl]-benzonitrile(17.2 mg, 0.0000400 mol) (21 mg TFA salt), was dissolved in DCM (10 mL)and cooled to 0° C. To this mixture was added MCPBA (18 mg, 0.0000800mol). The resulting mixture was stirred for 1 h at 0° C., and then for16 h at rt. HPLC and LCMS showed 80 area % product, and 3 area %sulfoxide. The MCPBA was removed using a sat'd NaHCO₃ wash, and theresulting washed mixture was concentrated by roto-evaporation. Theproduct was isolated by prep HPLCMS using a 19 mm×100 mm C18 column; 23%CH₃CN—H₂O (0.1% TFA), 1.0 min, to 43% at 6 min; 30 mL/min; detector setat m/z 447 nm; retention time, 5.1 min. The product was isolated fromthe eluent by freeze-drying. The yield was 5 mg of the TFA salt. ¹H NMR(d₆-DMSO) δ 12.70 (br s, 1H, NH); 8.83 (s, 1H); 8.82 (s, 1H); 8.41 (s,1H); 8.21 (dd, 1H); 8.16 (dd, 1H); 8.01 (td, 1H); 7.95 (td, 1H); 7.78(s, 1H); 7.19 (s, 1H); 4.34 (m, 1H, NCH); 3.62 (d, 2H); 2.28 (m, 1H);2.10 (m, 2H); 1.90 (m, 2H); 1.72 (m, 4H). MS(ES) 447 (M+1).

Example 689:3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylacetonitriletrifluoroacetate

Step 1:3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-cyclohexanone

To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(309 mg, 0.980 mmol) in ACN (6 mL) was added 2-cyclohexen-1-one (190 μL,01.96 mmol), followed by DBU (40 μL, 0.3 mmol). The resulting mixturewas stirred for one hour at which point LCMS indicated completeaddition. The mixture was reduced in vacuo and the crude product waspurified by column chromatography to obtain the product (397 mg, 98%).¹H NMR (400 MHz, CDCl₃): δ 8.84 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H),7.45 (d, 1H), 6.79 (d, 1H), 5.67 (s, 2H), 4.61 (m, 1H), 3.55 (m, 2H),3.05-2.90 (m, 2H), 2.45-2.30 (m, 4H), 2.05 (m, 1H), 1.90 (m, 1H), 0.92(m, 2H), −0.06 (s, 9H). MS (EI) m/z=412.2 (M+H).

Step 2:(2E,Z)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile

To a solution of t-BuOK in THF (1.0 M, 0.255 mL, 0.255 mmol) at 0° C.was added a solution of diethyl cyanomethylphosphonate (43 μL, 0.27mmol) in THF (0.6 mL) dropwise. The reaction was held for 10 minutes,then a solution of3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanone(100.0 mg, 0.2430 mmol) in THF (0.34 mL) was added dropwise. Aftercomplete addition, the cooling bath was removed and the reaction washeld at ambient temperature for 16 hours, at which point LCMS indicatedcomplete addition to yield the desired product as a mixture of E and Zisomers (87.9 mg, 83%). ¹H NMR (400 MHz, CDCl₃): δ 8.84 (s, 0.5H), 8.83(s, 0.5 H), 8.27 (d, 1H), 8.25 (s, 1H), 7.40 (s, 0.5H), 7.39 (s, 0.5H),6.81 (d, 0.5H), 6.79 (d, 0.5H), 5.67 (s, 2H), 5.28 (s, 0.5H), 5.24 (s,0.5H), 4.4 (m, 1H), 3.55 (m, 2H), 3.1-2.8 (m, 2H), 2.5-2.1 (m, 6H), 0.92(m, 2H), −0.06 (s, 9H). MS (EI) m/z=435.2 (M+H).

Step 3:3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-cyclohexylacetonitrile

To (2E,Z)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile(42.0 mg, 0.0966 mmol) was added THF (0.5 mL). The resulting solutionwas cooled to −78° C., and then 1.0 M L-Selectride® in THF (120 μL, 0.12mmol) was added dropwise. The reaction was held at −78° C. for 1 h atwhich point LCMS indicated complete reduction. The reaction was quenchedat −78° C. by addition of saturated aqueous NH₄Cl and EtOAc, and wasthen allowed to warm to ambient temperature. The phases were separatedand the aqueous phase was extracted with additional EtOAc. The combinedorganic phase was washed with water, then saturated NaCl, and then wasdried over MgSO₄. The crude product was purified by columnchromatography to obtain the product (26.5 mg, 63%). ¹H NMR (400 MHz,CDCl₃): δ 8.84 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.39 (d, 1H), 6.81(d, 1H), 5.67 (s, 2H), 4.53 (m, 1H), 3.52 (m, 2H), 2.6-1.4 (m, 11H),0.92 (m, 2H), −0.06 (s, 9H). MS (EI) m/z=437.2 (M+H).

Step 4:3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylacetonitriletrifluoroacetate

To3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylacetonitrile(30.1 mg, 0.0689 mmol) was added DCM (1.0 mL) and TFA (1.0 mL). Theresulting mixture was stirred for 1 hour at ambient temperature, atwhich point LCMS indicated complete cleavage to the N-hydroxymethylintermediate. The solvent was removed and to the residue was addedmethanol (1.0 mL) followed by ethylenediamine (37 μL, 0.55 mmol), afterwhich the reaction was stirred for 5 hours, at which point LCMSindicated complete reaction. The solvent was removed and the residue waspurified by preparative LCMS to provide the product as a TFA salt (24mg, 83%). ¹H NMR (400 MHz, CD₃OD): δ 8.91 (s, 1H), 8.82 (s, 1H), 8.45(s, 1H), 7.84 (s, 1H), 7.31 (s, 1H), 4.69 (s, 1H), 2.58 (d, 2H), 2.5-1.5(m, 9H). MS (EI) m/z=307.10 (M+H).

Example 690:5-({cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexyl}thio)-1H-1,2,4-triazol-3-aminebis(trifluoroacetate)

Step 1:trans-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanol

A solution of4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanone(662 mg, 1.61 mmol) in THF (5 mL) was cooled to 0° C. and lithiumtetrahydroaluminate (2M in THF, 0.804 mL, 1.61 mmol) was added slowly.The mixture was allowed to warm slowly to ambient temperature until LCMSindicated complete reduction. The reaction was cooled to 0° C. andquenched with dropwise addition of water (0.5 mL). DCM was added, andthe mixture was stirred for 1 hour at ambient temperature, after whichthe precipitated solids were removed by filtration. The filtrate wasreduced in vacuo to leave a white solid (0.63 g, 99%). HPLC of the solidshowed an approximately 4:1 ratio of trans to cis product. Tlc (6:3:1EtOAc:hexanes:isopropanol) gave an Rf of 0.25 for the cis product, and0.18 for the trans product. The product was purified by flashchromatography on silica gel to recover 230 mg of the pure trans alcoholand 25 mg pure of the cis alcohol, and 350 mg of mixed isomers.

¹H NMR (400 MHz, CDCl₃): δ 8.83 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H),7.39 (d, 1H), 6.81 (d, 1H), 5.67 (s, 2H), 4.24 (m, 1H), 3.79 (m, 1H),3.54 (m, 2H), 2.28 (m, 2H), 2.17 (m, 2H), 1.94 (m, 2H), 1.53 (m, 2H),0.92 (m, 2H), −0.06 (s, 9H). MS (EI) m/z=414 (M+H).

Step 2: trans-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethanesulfonate

Totrans-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanol(154 mg, 0.372 mmol) was added DCM (1.0 mL) and TEA (73 μL, 0.52 mmol).The resulting solution was then cooled to 0° C. and methanesulfonylchloride (34 μL, 0.45 mmol) was added. The reaction was held for 2hours, at which point tlc and LCMS indicated complete reaction. Thereaction was partitioned between water and DCM, the phases wereseparated and the aqueous phase was extracted with additional solvent.The combined organic phase was washed with water, then saturated NaCl,then was dried over MgSO₄ and reduced in vacuo to give the crude productwhich was used without further purification (173 mg, 95%). ¹H NMR (400MHz, CDCl₃): δ 8.83 (s, 1H), 8.24 (s, 2H), 8.24 (s, 1H), 7.39 (d, 1H),6.80 (d, 1H), 5.67 (s, 2H), 4.77 (m, 1H), 4.27 (m, 1H), 3.54 (m, 2H),3.06 (s, 3H), 2.36 (m, 4H), 2.03 (m, 2H), 1.82 (m, 2H), 1.53 (m, 2H),0.92 (m, 2H), −0.06 (s, 9H). MS (EI) m/z=492.1 (M+H).

Step 3:5-({cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexyl}thio)-1H-1,2, 4-triazol-3-amine bis(trifluoroacetate)

To a solution oftrans-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethanesulfonate (42 mg, 0.085 mmol) in DMF (800 μL) was added3-amino-1H-1,2,4-triazole-5-thiol (30 mg, 0.26 mmol) and K₂CO₃ (36 mg,0.26 mmol). The reaction was sealed and held at 100° C. for 2 hours atwhich point LCMS indicated conversion to desired product. The reactionwas diluted with water and extracted successively with ether, ethylacetate, and 3:1 chloroform:isopropyl alcohol. The combined organicphase was washed with water, then saturated NaCl, dried over MgSO₄ andreduced in vacuo, and the crude product was purified by columnchromatography to give5-({cis-4-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexyl}thio)-1H-1,2,4-triazol-3-amine(27.3 mg, 63%). To the product was added DCM (0.5 mL) and TFA (0.5 mL),and the reaction was stirred for 1 hour at ambient temperature at whichpoint LCMS indicated complete cleavage to the N-hydroxymethylintermediate. The solvent was removed and to the residue was addedmethanol (1.0 mL) followed by NH₄OH (0.3 mL), the reaction was stirredfor 16 hours at which point LCMS indicated complete deprotection. Thesolvent was removed and the residue was purified by preparative LCMS toprovide the product as a bis-TFA salt (15.1 mg, 29%). ¹H NMR (400 MHz,CD₃OD): δ 8.77 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 7.74 (d, 1H), 7.21(d, 1H), 4.40 (m, 1H), 3.97 (m, 1H), 2.25 (m, 2H), 2.04 (m, 6H). MS (EI)m/z=382.2 (M+H).

Example 691:N-{5-[({cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexyl}-methyl)thio]-4H-1,2,4-triazol-3-yl}methanesulfonamidetrifluoroacetate

Step 1.N-5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-ylmethanesulfonamide

5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-amine(30.00 mg, 5.706E-5 mol) was dissolved in DCM (2.00 mL, 0.0312 mol) withTEA (0.024 mL, 0.00017 mol) and was cooled at 0° C. To the reaction wasadded methanesulfonyl chloride (0.0066 mL, 0.000086 mol) and theresulting mixture was stirred at 0° C. for 60 minutes, at which timeLCMS analysis showed mostly product. The reaction was chromatographed onsilica gel using EtOAc as eluent to give the product. LC/MS (M+1)⁺:604

Step 2.N-5-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-ylmethanesulfonamide

Into a 1-neck round-bottom flask [A]N-5-[(cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-ylmethanesulfonamide(0.025 g, 0.000041 mol) was dissolved in DCM (3.00 mL, 0.0468 mol) andTFA (mL, 0.006 mol) was added. The reaction was stirred at 25° C. for 16hours at which time LCMS analysis showed no starting material present.The reaction was concentrated using a rotary evaporator and wasdissolved in methanol (2.00 mL, 0.0494 mol) and 16 M ammonia in water(0.2 mL) was added. The reaction was stirred at 25° C. for 3 hours atwhich time LCMS analysis showed no starting material present. Thereaction was concentrated using a rotary evaporator and was purified byprep LC to give the product as the trifluoroacetate salt. LC/MS(M+1)⁺:474, 1H NMR (CD₃OD): 8.87 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H),7.85 (d, 1H), 7.33 (d, 1H), 4.48 (m, 1H), 3.36 (s, 3H), 3.23 (d, 2H),2.30 (m, 2H), 2.04 (m, 3H), 1.85 (m, 4H).

Example 692:[cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1H-1,2,4-triazol-1-yl)cyclohexyl]acetonitrile

1H-1,2,4-Triazole (91.0 mg, 0.00132 mol), DBU (174 μL, 0.00070 mol), [A]4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile (86.4 mg, 0.000199 mol), and ACN (2.0 mL)were stirred at rt. After 4d, LCMS showed about 58 area % product (twopeaks, M+H 504, ratio 1:1). The DBU in the reaction was neutralized withTFA. The product was isolated by prep HPLC using a 30 mm×100 mm C18column; 32% CH₃CN—H₂O (0.1% TFA), 1 min, to 47% at 6 min; 60 mL/min;detector set at 254 nm; retention time, 5.1(A) & 5.4 (B) min. The eluentwas concentrated using a rotary evaporator to give 22 mg of (A) & 36 mgof (B).

Deprotection: The products were dissolved separately in TFA (0.5 mL) andstirred for 1 h. LCMS showed conversion to the hydroxymethyl derivative(M+H 404). The solutions were concentrated using a rotary evaporator toremove TFA. Methanol was added, and the resulting mixtures wereconcentrated again. The resulting residue was dissolved in methanol (1mL), and ammonium hydroxide (0.25 mL) added. The solution was stirred0.5 h. LCMS showed complete de-protection (M+H 374) and the mixture wasthen concentrated by roto-evaporation. Each isomer was isolated by prepHPLCMS using a 19 mm×100 mm C18 column; 15% CH₃CN—H₂O (0.1% TFA), 1.5min, to 32% at 6 min; 30 mL/min; detector set at m/z 374; retentiontime, 4.5 min (A) & 4.7 min (B). The eluates were freeze dried. Yield 13mg isomer A and 24 mg isomer B (TFA salts, white solids). NMR analysis(including NOE & COSY) was consistent with expectation for thestructures, with A=cis, and B=trans. NMR (d₆-DMSO) δ cis: 12.94 (br s,1H, NH); 8.95 (s, 1H); 8.87 (s, 1H); 8.81 (s, 1H); 8.42 (s, 1H); 8.14(s, 1H); 7.85 (m, 1H); 7.22 (m, 1H); 4.48 (m, 1H, NCH); 3.12 (s, 2H);2.84 (m, 2H); 2.07 (m, 4H); 1.69 (m, 2H). MS(ES) 374 (M+1). trans: 12.85(br s, 1H, NH); 8.94 (s, 1H); 8.89 (s, 1H); 8.84 (s, 1H); 8.47 (s, 1H);8.11 (s, 1H); 7.84 (m, 1H); 7.26 (m, 1H); 4.50 (m, 1H, NCH); 3.48 (s,2H); 2.42-2. 10 (m, 8H). MS(ES) 374 (M+1).

Example 705:3-1-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-yn-1-yl-benzonitriletrifluoroacetate

Step 1:3-{1-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-yn-1-yl}benzonitrile

1 M Diisobutylaluminum hydride in hexane (0.31 mL) was added dropwise toa solution of methyl3-(3-cyanophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate(100 mg, 0.0002 mol) (prepared by using a procedure analogous to Example712, Step 1) in DCM (3 mL, 0.05 mol) and the mixture was cooled to −78°C. The reaction mixture was stirred at −78° C. for 4 h and was afterwardquenched with cold methanol (3 mL, 0.07 mol). The reaction was allowedto warm to 0° C. and potassium carbonate (60 mg, 0.0004 mol) andBestmann-Ohira reagent (1.5 eq, 57 mg) (E. Quesada et al, Tetrahedron,62 (2006) 6673-6680) were added. The reaction was stirred at roomtemperature overnight, and then partitioned between ethyl acetate andwater. The organic layer was washed with saturated NaCl, dried overMgSO₄, filtered and concentrated to give the crude product. The crudeproduct was purified using silica gel (EtOAC/Hexane 1:3 to 1:1) to givethe desired product,3-{1-[4-(7-{[2-(trimethylsilyl)ethoxy]-methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-yn-1-yl}benzonitrile(40 mg of mixture). m/z=469 (M+1).

Step 2:3-1-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-yn-1-ylbenzonitriletrifluoroacetate

Using a procedure analogous to Example 712, Step 4, the title compoundwas prepared (4.5 mg, 46%) as an amorphous white solid. ¹H NMR (500 MHz,DMSO): δ □12.5 (b, 1H), 9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 8 (s, 1H),7.8 (m 2H), 7.7 (s, 1H), 7.6 (m, 1H), 7 (m, 1H), 5.9 (m, 1H), 3.4 (dd,1H), 3.2 (dd, 1H), 2.9 (s, 1H). m/z=339 (M+1).

Example 706:3-{1-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-yn-1-yl}benz-aldehydetrifluoroacetate

Using the procedure of Example 705, the title compound was prepared as asecondary product (4.5 mg, 46%) as an amorphous white solid. ¹H NMR (400MHz, CDCl₃): δ□ 10 (s, 1H), 9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 8 (s,1H), 7.9 (m 1H), 7.8 (m, 1H), 7.7 s, 1H), 7.6 (m, 1H), 7.1 (s, 1H), 5.9(m, 1H), 3.4 (dd, 1H), 3.2 (dd, 1H), 2.9 (s, 1H). m/z=342.

Example 712:4-[1-(3-Methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate

Step 1: Methyl3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate

A solution of methyl (2E)-3-phenylacrylate (500 mg, 0.003 mol) in ACN (2mL, 0.04 mol) was slowly added to a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(0.5 g, 0.002 mol) in ACN (2 mL, 0.04 mol) and DBU (500 μL, 0.003 mol).The reaction was stirred at room temperature over the weekend. Thereaction was partitioned between water and EtOAc. The organic layer waswashed with saturated sodium chloride, dried over MgSO₄, filtered andconcentrated to give an oil. The product was purified by FCC on silicagel using EtOAc/Hexane (1:2 to 1:1) gave methyl3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate(500 mg, 70%) as a semisolid residue.

¹H NMR (400 MHz, CDCl₃): δ □□8.9 (s, 1H), 8.4 (s, 2H), 7.4 (m, 5H), 6.8(d, 1H), 6 (m, 1H), 5.7 (s, 2H), 3.7-3.8 (m, 3H), 3.6 (m, 2H), 2.2 (m,1H), 1.4 (m, 2H), 1.1 (m, 2H), 0.02 (s, 9H), m/z=478 (M+1).

Step 2:3-Phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol

Diisobutylaluminum hydride in hexane (1 M, 0.69 mL) was added to asolution of methyl 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanoate(150 mg, 0.00031 mol) in DCM (3 mL, 0.05 mol) and the mixture was cooledto −78° C. under a nitrogen atmosphere. The reaction was stirred for 1 hat −78° C. and was allowed to warm to room temperature for 4 hrs. Thereaction was quenched with methanol (100 μL), and saturated ammoniumchloride (100 μL), and then taken up in ethyl acetate dried over MgSO₄and filtered. The filtrate was concentrated to give3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol(130 mg, 92%) as an oil. m/z=450 (M+1).

Step 3:4-[1-(3-Methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

Sodium hydride (9.6 mg, 0.00040 mol) was added to a solution of3-phenyl-3-[4-(7-[2-(tri-methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol(120 mg, 0.00027 mol) in DMF (3 mL, 0.04 mol) and the mixture was cooledto 0° C. The reaction was stirred for 20 min and methyl iodide (22 μL,0.00035 mol) was added. The reaction was allowed to warm to roomtemperature and stirred overnight. The reaction was partitioned betweenwater and EtOAc. The organic layer was washed with saturated NaCl, driedover MgSO₄, filtered and concentrated to give4-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(100 mg, 88%) as a semisolid. m/z=464 (M+1).

Step 4:4-[1-(3-Methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate

Trifluoroacetic Acid (2 mL, 0.02 mol) was added to a mixture of4-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(80 mg, 0.0002 mol) in DCM (3 mL, 0.05 mol) at room temperature. Thestarting material was consumed after stirring for 2 hrs and the reactionsolution was concentrated to remove the TFA. The crude reaction wasdiluted with methanol (3 mL, 0.07 mol) and was treated withethylenediamine (0.3 mL, 0.004 mol) at room temperature. The reactionmixture was stirred for 18 hs and was concentrated and purified usingHPLC on a C-18 column eluting with an ACN: water gradient containing0.2% TFA, to give the title compound (43 mg, 60%) as a white amorphoussolid. ¹H NMR (400 MHz, CDCl₃): δ□8.9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H),7.8 (s, 1H), 7.4 (m, 1H), 7.3 (m, 5H), 7.2 (b, 1H), 5.7 (m, 1H), 3.3 (m,1H), 3.2 (s, 3H), 2.7 (m, 1H), 2.4 (m, 1H). m/z=334 (M+1).

Example 715:3-1-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-en-1-ylbenzonitriletrifluoroacetate

A mixture of[4-1-[1-(3-bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]-pyrimidine(20 mg, 0.00005 mol) in DMF (2 mL, 0.02 mol) and zinc cyanide (60 mg,0.0005 mol) was degassed with a nitrogen stream. The mixture was thentreated with tetrakis(triphenyl-phosphine)palladium(0) (40 mg, 0.00003mol), again degassed with nitrogen, and was then heated in a microwavereactor to 170° C. for 15 min. The reaction was allowed to cool, wasfiltered and purified by HPLC on a C-18 column eluting with anACN/water/TFA gradient to give the title compound (10 mg, 40%) as awhite amorphous solid.

¹H NMR (400 MHz, DMSO): δ□ 8.9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 7.9(s, 1H), 7.8 (m, 3H), 7.6 (m, 1H), 7.1 (b, 1H), 5.6-5.8 (m, 2H), 5.1 (d,1H), 5 (d, 1H), 3.3 (m, 1H), 3 (m, 1H). m/z=341 (M+1).

Example 716:4-1-[1-(3-Bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]-pyrimidine

Step 1:3-(3-Bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal

Diisobutylaluminum hydride in hexane (1 M, 4 mL) was added to a −78° C.solution of ethyl3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate(600 mg, 0.001 mol) in DCM (6 mL, 0.09 mol). After stirring for 4 h, thereaction was quenched with cold methanol (300 μL), and then saturatedammonium chloride (500 μL) was added and the resulting solution wasstirred for 1 h. The reaction was partitioned between water and EtOAc.The organic layer was washed with brine, dried over MgSO₄, filtered andconcentrated. The product was purified by flash chromatography on silicagel eluting with hexane: EtOAc, (2:1 to 1:2), to give3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal(400 mg, 70%) as an oil. ¹H NMR (400 MHz, CDCl₃): δ 9.9 (s, 1H), 8.9 (s,1H), 8.4 (s, 2H), 7.6 (d, 1H), 7.5 (d, 1H), 7.4 (d, 1H), 7.3-7.4 (m,2H), 6.8 (d, 1H), 6.1 (m, 1H), 5.7 (s, 2H), 4 (m, 1H), 3.6 (m, 2H), 3.3(dd, 1H), 1.0 (m, 2H), 0.01 (s, 9H). m/z=526, 528 (M+1).

Step 2:4-1-[1-(3-Bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-yl-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

Potassium tert-butoxide in THF (!M, 200 μL) was added to a solution ofmethyltriphenyl-phosphonium iodide (80 mg, 0.0002 mol) in THF (2 mL,0.02 mol) at 0° C. The reaction was stirred at room temperature for 1 hand then cooled to −78° C. The3-(3-bromophenyl)-3-[4-(7-[2-(trimethyl-silyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal(90 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) was added dropwise. Thereaction was allowed to warm to room temperature gradually. The reactionwas partitioned between water and EtOAc. The organic layer was washedwith saturated NaCl, dried over MgSO₄, filtered and concentrated to givean oil. The product was purified by FCC on silica gel eluting withEtOAc:Hexane, (1:1) to give4-1-[1-(3-bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-yl-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(35 mg, 40%) as an oil. m/z=524, 526 (M+1).

Step 3:4-1-[1-(3-Bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrimidine

Using a procedure analogous to Example 712, Step 4, but using4-1-[1-(3-bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-yl-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinethe title compound was prepared (10 mg, 30%) as a white amorphous solid,¹H NMR (400 MHz, DMSO): δ□ 8.9 (s, H), 8.8 (s, H), 8.4 (s, H), 7.8 (s,H), 7.7 (s, H), 7.5 (m, 2H), 7.3 (m, H), 7.1 (s, H), 5.7 (m, 2H), 5.2(d, 1H), 5.0 (d, 1H), 3.2 (m, 1H), 3.0 (m, 1H). m/z=394, 396 (M+1).

Example 717:3-(4,4-Difluoro)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-en-1-ylbenzonitrile

Step 1:4-{1-[1-(3-Bromophenyl)-4,4-difluorobut-3-en-1-yl]-1H-pyrazol-4-yl}-7-{[2-(trimethylsilyl)-ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

To a solution of3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal(0.05 g, 0.00009 mol) in N,N-dimethylacetamide (2 mL, 0.02 mol) wasadded triphenylphosphine (0.1 g, 0.0006 mol), dibromodifluoromethane (50uL, 0.0006 mol) and 0.76 M zinc in THF (0.7 mL). The reaction wasstirred at room temperature for 18 hs. The reaction was partitionedbetween water and EtOAc. The organic layer was washed with saturatedNaCl, dried over MgSO₄, filtered and concentrated to give an oil. Theproduct was purified by FCC on silica gel eluting with EtOAc, Hexane(1:2) to give4-{1-[1-(3-bromophenyl)-4,4-difluorobut-3-en-1-yl]-1H-pyrazol-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine(20 mg, 40%) as a clear oil. m/z=560, 562 (M+1).

Step 2:4-1-[1-(3-Bromophenyl)-4,4-difluorobut-3-en-1-yl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]-pyrimidine

Using a procedure analogous to Example 712, Step 4, but using4-{1-[1-(3-bromophenyl)-4,4-difluorobut-3-en-1-yl]-1H-pyrazol-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine,the compound4-1-[1-(3-bromophenyl)-4,4-difluorobut-3-en-1-yl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrimidinewas prepared (30 mg, 99%) as an oil. m/z=430, 432 (M+1).

Step 3:3-4,4-Difluoro-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-en-1-ylbenzonitrile

A mixture of4-1-[1-(3-bromophenyl)-4,4-difluorobut-3-en-1-yl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrimidine(30 mg, 0.00007 mol) in DMF (2 mL, 0.02 mol) and zinc cyanide (80 mg,0.0007 mol) was degassed with nitrogen. The mixture was then treatedwith tetrakis(triphenyl-phosphine)palladium(0) (50 mg, 0.00004 mol) andwas degassed with nitrogen, and then was heated in microwave at 170° C.for 15 min. The reaction was then allowed to cool, filtered and purifiedby HPLC on a C-18 column eluting with an ACN/water/TFA gradient to givethe title compound (10 mg, 30%) as a white amorphous solid. ¹H NMR (400MHz, DMSO): δ□8.9 (s, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 7.9 (s, 1H),7.7-7.8 (m, 3H), 7.5 (m, 1H), 7.1 (m, 1H), 5.7 (m, 1H), 4.3-4.4 (m, 1H),3.1 (m, 1H), 2.9 (m, 1H). m/z=377 (M+1).

The following compounds in Table 14 were prepared as indicated in thecolumn labeled “Prep. Ex. No.” and the details of certain exemplarysynthetic procedures are provided following Table 14.

TABLE 14

Ex. MS Prep. No. Structure of R (M + H) Name Ex. No. 727

308 4-[1-(1-cyclopentylbut-3-en-1- yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine- trifluoroacetate salt 727 728

254 4-[1-(1-methylbut-3-en-1-yl)-1H- pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidine□trifluoroacetate salt 727 729

452 4-[1-(1-cyclopentyl-2- cyclopropylethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]- pyrimidine□trifluoroacetate salt 727 730

306 4-[1-(1-cyclopentylbut-3-yn-1- yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine □trifluoroacetate salt 727 731

310 4-[1-(1-cyclopentylbutyl)-1H- pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidine□trifluoroacetate salt 729 732

344 4-[1-(1-cyclopentyl-4,4- difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]- pyrimidine□trifluoroacetate salt 727733

346 4-1-[4,4-difluoro-1-(tetrahydro- furan-3-yl)but-3-en-1-yl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]- pyrimidine trifluoroacetate salt 727Step 3 & 4, then 731, step 1* 734

254 4-[1-(1-methylbut-3-en-1-yl)-1H- pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidine trifluoroacetate salt 727 Step 3 & 4, then 731 735

316 4-[1-(1-cyclopropyl-4,4-difluoro- but-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 727 Step 3 & 4, then731 736

346 4-[1-(1-cyclopentyl-4,4-difluoro- butyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 731 737

321 3-(1-methylcyclopentyl)-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propane- nitrile trifluoroacetate salt 737 738

295 (3R)-and (3S)-4,4-dimethyl-3- [4-(7-[2-(trimethylsilyl)ethoxy]-methyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile trifluoroacetate 737 salt 739

304 1-2-cyano-1-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylcyclopropanecarbonitrile trifluoroacetate salt 739 740

440 N-[(1-2-cyano-1-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylcyclo- pentyl)methyl]benzamide 740 741

427 3-1-[(Benzyloxy)methyl]cyclo- pentyl-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazole-1- yl]propanenitrile trifluoroacetate salt741 742

386 3-[1-(methylsulfonyl)pyrrolidin- 3-yl)-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1- yl]propanenitrile trifluoroacetate salt742 743

375 N′-cyano-4-(cyanomethyl)-4-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidine-1- carboximidamide 743 744

348 4-1-[2,2,2-trifluoro-1-(1H- imidazol-2-ylmethyl)ethyl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d- pyrimidine 744 745

379 4-(1-(1R)-2,2,2-trifluoro-1-[(4- methyl-1,3-thiazol-2-yl)-methyl]ethyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine 745 746

306 4-1-[1-(trifluoromethyl)but-3-yn- 1-yl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrimidine 730 747

308 4-1-[1-(trifluoromethyl)but-3-en- 1-yl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrimidine 727 748

310 4-1-[1-(trifluoromethyl)butyl]- 1H-pyrazol-4-yl-7H-pyrrolo-[2,3-d]pyrimidine 731 749

344 4-1-[4,4-difluoro-1-(trifluoro- methyl)but-3-en-1-yl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]- pyrimidine 732 750

346 4-1-[4,4-difluoro-1-(trifluoro- methyl)butyl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrimidine 731 *Step 1 of example 731 was modified asfollows: The Ph₃P and CF₂Br₂ were combined in DMAC at 0° C. and thenallowed to warm to room temperature until the ylid formation wascomplete as determined by LCMS. The solution of the ylid was thenre-cooled to 0° C. and the aldehyde and zinc were added to the ylidsolution and the reaction was slowly warmed to room temperature.

Example 727:4-[1-(1-Cyclopentylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate salt

Step 1: (2E)-3-Cyclopentylacrylic acid

To a solution of malonic acid (1.06 g, 10.2 mol) in pyridine (1.25 mL)was added piperidine (0.15 mL) and cyclopentanecarbaldehyde (1.00 g,10.2 mmol). The mixture was heated to 40° C. for 2 hours, followed bystirring at room temperature for 16 hours. The mixture was then cooledin an ice bath and 2N HCl was added to acidify. The product wasextracted with ether. The ether extract was washed with aq. HCl andbrine, dried over sodium sulfate, filtered, and the solvent was removedin vacuo to afford the product (1.30 g, 77%), which was used withoutfurther purification.

¹H NMR (300 MHz, CDCl₃): δ□7.06 (dd, 1H), 5.80 (dd, 1H), 2.70-2.54 (m,1H), 1.93-1.32 (m, 8H); MS(ES): 141 (M+H).

Step 2. Methyl (2E)-3-cyclopentylacrylate

To a solution of (2E)-3-cyclopentylacrylic acid (1.3 g, 9.3 mmol) in DCM(65 mL) at 0° C. was added oxalyl chloride (3.1 mL, 37 mmol), dropwise.The resulting solution was stirred at 0° C. for 40 minutes, then at roomtemperature for 2 hours. The volatiles were evaporated to afford(2E)-3-cyclopentylacryloyl chloride as a colorless liquid. A portion ofthis (2E)-3-cyclopentylacryloyl chloride (0.75 g, 4.7 mol) was dissolvedin methanol (10 mL) and the resulting solution was stirred for 2 hours.The solvent was evaporated to afford the product (700 mg, 96%).

¹H NMR (300 MHz, CDCl₃): δ□6.94 (dd, 1H), 5.79 (dd, 1H), 3.71 (s, 3H),2.66-2.50 (m, 1H), 1.92-1.27 (m, 8H).

Step 3. Methyl3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate

To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(2.9 g, 9.2 mmol) and methyl (2E)-3-cyclopentylacrylate (1.70 g, 11.0mmol) in ACN (100 mL), was added DBU (2.7 mL, 18 mmol). The resultingmixture was stirred for 96 hours. The ACN was removed in vacuo, and theresulting residue was dissolved in ethyl acetate. This solution waswashed with 1.0 N HCl, followed by brine, and then dried over sodiumsulfate, and the solvent removed in vacuo. Flash column chromatography(eluting with a gradient from 0-70% ethyl acetate in hexanes) affordedthe product (2.73 g, 63%).

¹H NMR (300 MHz, CDCl₃): δ □8.84 (s, 1H), 8.28 (s, 2H), 7.39 (d, 1H),6.81 (d, 1H), 5.67 (s, 2H), 4.46 (dt, 1H), 3.60 (s, 3H), 3.54 (t, 2H),3.18 (dd, 1H), 2.89 (dd, 1H), 2.59-2.42 (m, 1H), 1.95-1.80 (m, 1H),1.75-1.10 (m, 7H), 0.92 (t, 2H), −0.06 (s, 9H); MS(ES):470 (M+H).

Step 4.3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal

To a solution of methyl3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate(0.501 g, 1.07 mmol) in THF (5.0 mL) at −78° C. was added 1.00 Mdiisobutylaluminum hydride in DCM (2.35 mL) dropwise. The reaction wasstirred with gradual warming to −10° C. over the course of 2 hours. Atthis temperature, a further portion of 1.0 M diisobutylaluminum hydridein DCM (1.50 mL) was added. When the reaction was determined to becomplete by LCMS, a saturated solution of K/Na tartrate was added,followed by ether. The resulting mixture was stirred for two hours atroom temperature. The organic layer was separated and washed with water,and brine, then dried over sodium sulfate and the solvent was removed invacuo to give a viscous oil, which was used without furtherpurification.

MS(ES):442 (M+H).

To a solution of oxalyl chloride (0.108 mL, 1.28 mmol) in DCM (10.0 mL)at −78° C. was added DMSO (151 μL, 2.13 mmol). After stirring for 5minutes,3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol(471 mg, 1.07 mmol) in DCM (3.00 mL) was added. The mixture was stirredfor 30 minutes at −78° C. TEA (594 μL, 4.26 mmol) was then added. Theresulting mixture was then allowed to warm to room temperature over thecourse of 30 minutes. Water was added, and the layers were separated.The organic layer was washed successively with 0.1 N HCl, water,saturated sodium bicarbonate solution, and brine, and was then driedover sodium sulfate and the solvent was removed in vacuo. Flash columnchromatography (eluting with a gradient of 0-60% ethyl acetate inhexanes) afforded the product (384 mg, 82%).

¹H NMR (300 MHz, CDCl₃): δ 9.73 (s, 1H), 8.87 (s, 1H), 8.71 (br s, 1H),8.30 (s, 1H), 7.47 (br s, 1H), 6.88 (br s, 1H), 5.69 (s, 2H), 4.66-4.49(m, 1H), 3.54 (t, 2H), 3.40 (ddd, 1H), 2.95 (ddd, 1H), 2.55-2.44 (m,1H), 2.01-1.21 (m, 8H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):440 (M+H).

Step 5.4-[1-(1-Cyclopentylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 1.0 M potassium tert-butoxide in THF (0.207 mL) in THF(2.0 mL) at 0° C. was added triphenylmethylphosphonium bromide (77.8 mg,0.218 mmol). The resulting mixture was warmed to room temperature andallowed to stir for 30 minutes. A solution of3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal(0.100 g, 0.228 mmol) in THF (2.0 mL) was added. After 30 minutes, themixture was quenched by the addition of saturated ammonium chloridesolution and the product was then extracted with ether. The etherextract was dried over sodium sulfate and the solvent was removed invacuo. Flash column chromatography (eluting with a gradient of 0-40%ethyl acetate in hexanes) afforded the product (40 mg, 44%).

¹H NMR (400 MHz, CDCl₃): δ 8.84 (s, 1H), 8.26 (s, 1H), 8.19 (br s, 1H),7.40 (s, 1H), 6.83 (br s, 1H), 5.67 (s, 2H), 5.60 (ddt, 1H), 5.01 (dq,1H), 4.97-4.93 (m, 1H), 3.99 (dt, 1H), 3.54 (t, 2H), 2.79-2.60 (m, 2H),2.60-2.40 (m, 1H), 1.99-1.89 (m, 1H), 1.75-1.41 (m, 5H), 1.37-1.12 (m,2H), 0.92 (t, 2H), −0.06 (s, 9H); MS(ES):438 (M+H).

Step 6.4-[1-(1-Cyclopentylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate salt

4-[1-(1-Cyclopentylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(13 mg, 0.030 mmol) was dissolved in DCM (3 mL) and TFA (0.5 mL) wasadded. The resulting solution was stirred at room temperature for 3hours. The solvent was removed in vacuo. The residue was dissolved inTHF (2 mL), and 6 N NaOH (1 mL) was added. The mixture was stirred atroom temperature for 1 hour, and then was partitioned between water andethyl acetate. The organic layer was dried over sodium sulfate and thesolvent was removed in vacuo. Purification via preparative-HPLC/MS (C18eluting with a gradient of H₂O and ACN containing 0.1% TFA) afforded theproduct (10 mg, 80%).

¹H NMR (400 MHz, d₆-DMSO): δ□12.73 (s, 1H), 8.88 (s, 2H), 8.43 (s, 1H),7.79 (t, 1H), 7.19 (dd, 1H), 5.60 (ddt, 1H), 5.00-4.93 (m, 1H),4.91-4.87 (m, 1H), 4.23 (dt, 1H), 2.76-2.59 (m, 2H), 2.47-2.34 (m, 1H),1.92-1.82 (m, 1H), 1.68-1.22 (m, 6H), 1.21-1.09 (m, 1H); MS(ES):308(M+H).

Example 729:4-[1-(1-Cyclopentyl-2-cyclopropylethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidine□trifluoroacetate salt

Step 1.4-[1-(1-Cyclopentyl-2-cyclopropylethyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate salt

A solution of4-[1-(1-cyclopentylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(prepared in Example 727, Step 5) (54.0 mg, 0.123 mmol) in DCM (1 mL)was added to a freshly prepared ethereal solution of excess CH₂N₂ heldat 0° C. Palladium acetate (10.0 mg, 0.044 mol) was added. Afterstanding for 2 hours, the excess CH₂N₂ was quenched by the addition ofacetic acid. The solution was then diluted with further DCM, washedsuccessively with saturated sodium bicarbonate solution, water, andbrine, and dried over sodium sulfate, and the solvent was removed invacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradientof H₂O and ACN containing 0.1% TFA) afforded the product (13 mg, 18%).

¹H NMR (300 MHz, CDCl₃): δ□ 9.05 (s, 1H), 8.81 (d, 1H), 8.35 (s, 1H),7.59 (t, 1H), 7.03 (t, 1H), 5.76 (s, 2H), 4.10 (t, 1H), 3.59 (t, 2H),2.57-2.36 (m, 1H), 2.15-2.00 (m, 1H), 2.00-1.83 (m, 1H), 1.79-1.40 (m,6H), 1.37-1.09 (m, 2H), 0.97 (t, 2H), 0.55-0.26 (m, 3H), 0.07-⁻0.15 (m,11H); MS(ES):452 (M+H).

Step 2.4-[1-(1-Cyclopentyl-2-cyclopropylethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidineQ trifluoroacetate salt

4-[1-(1-Cyclopentyl-2-cyclopropylethyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate salt (13 mg, 0.023 mol) was stirred at room temperaturein a solution of DCM (2 mL) containing TFA (1.5 mL) for two hours. Thesolvent was removed in vacuo. The resulting residue was redissolved inTHF (3 mL), and 6N NaOH (2 mL) was added. After stirring for one hour,the mixture was partitioned between water and ethyl acetate. The organiclayer was dried over sodium sulfate and the solvent was removed invacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradientof H₂O and ACN containing 0.1% TFA) afforded the product (9 mg, 90%).

¹H NMR (400 MHz, d₆-DMSO): δ□ 12.75 (s, 1H), 8.90 (s, 1H), 8.84 (s, 1H),8.47 (s, 1H), 7.81 (s, 1H), 7.22 (s, 1H), 4.19 (dt, 1H), 2.43-2.29 (m,1H), 2.03-1.92 (m, 1H), 1.88-1.76 (m, 1H), 1.68-1.37 (m, 5H), 1.35-1.08(m, 3H), 0.43-0.26 (m, 2H), 0.24-0.13 (m, 1H), 0.07-⁻0.03 (m, 1H),−0.14-⁻0.24 (m, 1H); MS(ES):322 (M+H).

Example 730:4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate salt

Step 1.4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of potassium carbonate (38.4 mg, 0.278 mmol) in methanol(2.0 mL) at 0° C. was added a solution of3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal(prepared as in Example 727, step 4) (61.0 mg, 0.139 mmol) in methanol(1.0 mL), followed by a solution of dimethyl(1-diazo-2-oxopropyl)phosphonate (40.0 mg, 0.208 mmol) in methanol (1.0mL). The mixture was slowly warmed to ambient temperature and stirredfor 16 hours. The mixture was then diluted with water and extracted withethyl acetate. The combined extracts were washed with water, saturatedammonium chloride, and then dried over sodium sulfate and the solventwas removed in vacuo to afford the product, which was used withoutfurther purification (52 mg, 86%).

¹H NMR (300 MHz, CDCl₃): δ 8.85 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H),7.41 (d, 1H), 6.84 (d, 1H), 5.67 (s, 2H), 4.14 (ddd, 1H), 3.53 (t, 2H),2.90 (ddd, 1H), 2.79 (ddd, 1H), 2.66-2.49 (m, 1H), 1.98 (t, 1H),2.00-1.88 (m, 1H), 1.78-1.44 (m, 5H), 1.39-1.11 (m, 2H), 0.92 (t, 2H),−0.06 (s, 9H); MS(ES):436 (M+H).

Step 2.4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidineD trifluoroacetate salt

A solution of4-[1-(1-cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(52 mg, 0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred for 2 hours.The solvents were removed in vacuo. The resulting residue was dissolvedin THF (3 mL) and 6N NaOH (2 mL) was added. After stirring for 1 hour,the mixture was partitioned between water and ethyl acetate. The organiclayer was dried over sodium sulfate and the solvent was removed invacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradientof H₂O and ACN containing 0.1% TFA) afforded product (30 mg, 60%).

¹H NMR (300 MHz, d₆-DMSO): δ □12.72 (s, 1H), 8.91 (s, 1H), 8.84 (s, 1H),8.47 (s, 1H), 7.80 (s, 1H), 7.19 (s, 1H), 4.34 (dt, 1H), 2.97-2.69 (m,3H), 2.50-2.32 (m, 1H), 1.93-1.77 (m, 1H), 1.70-1.09 (m, 7H); MS(ES):306(M+H).

Example 731:4-[1-(1-Cyclopentylbutyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine Dtrifluoroacetate salt

4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidinetrifluoroacetate salt (prepared in Example 729) (20 mg, 0.048 mmol) wasdissolved in methanol (2 mL) and a catalytic amount of 5% Pd—C wasadded. The mixture was stirred under 1 atmosphere of hydrogen via anaffixed balloon. After 2 hours, the mixture was filtered and purifiedvia preparative-HPLC/MS (C18 eluting with a gradient of H₂O and ACNcontaining 0.1% TFA) to afford the product (14 mg, 69%).

¹H NMR (400 MHz, d₆-DMSO): δ□ 12.73 (s, 1H), 8.86 (s, 1H), 8.83 (s, 1H),8.45 (s, 1H), 7.79 (t, 1H), 7.20 (d, 1H), 4.11 (dt, 1H), 2.43-2.26 (m,1H), 2.02-1.70 (m, 3H), 1.68-1.35 (m, 4H), 1.33-0.89 (m, 5H), 0.83 (t,3H); MS(ES):310 (M+H).

Example 732:4-[1-(1-Cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine□trifluoroacetate salt

Step 1.4-[1-(1-Cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidine

To a solution of3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal(prepared as in Example 727, Step 4) (181 mg, 0.41 mmol) inN,N-dimethylacetamide (3.6 mL) was added triphenylphosphine (294 mg,1.12 mmol) followed by dibromodifluoromethane (235 mg, 1.12 mmol).Rieke® Zinc (1.8 mL of a suspension of 2.5 g in 50 ml THF) was thenadded in one portion. The resulting mixture was stirred at roomtemperature for 4.5 hours. The mixture was filtered through diatomaceousearth. The filtrate was partitioned between ether and water. The etherlayer was washed with water, and brine, then dried over sodium sulfate,and the solvent was removed in vacuo. Flash column chromatography(eluting with a gradient from 0-30% ethyl acetate in hexanes) affordedproduct (104 mg, 53%).

¹H NMR (400 MHz, CDCl₃): δ□ 8.91 (s, 1H), 8.51 (br s, 1H), 8.34 (s, 1H),7.51 (d, 1H), 6.93 (d, 1H), 5.74 (s, 2H), 4.05 (ddd, 1H), 4.04-3.96 (m,1H), 3.60 (t, 2H), 2.78-2.62 (m, 2H), 2.58-2.45 (m, 1H), 2.07-0.87 (m,10H), 0.00 (s, 9H); MS(ES):474 (M+H).

Step 2.4-[1-(1-Cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine□ trifluoroacetate salt

A solution of4-[1-(1-cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(tri-methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(41 mg, 0.086 mmol) in DCM (3 mL) and TFA (1.5 mL) was stirred for twohours at room temperature. The solution was then concentrated in vacuo.The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL)was added. After stirring for 1 hour, the mixture was partitionedbetween water and ethyl acetate. The organic layer was dried over sodiumsulfate and the solvent was removed in vacuo. Purification viapreparative-HPLC/MS (C18 eluting with a gradient of H₂O and ACNcontaining 0.1% TFA) afforded the desired product (39 mg, 98%).

¹H NMR (400 MHz, d₆-DMSO): δ□ 12.72 (s, 1H), 8.84 (s, 1H), 8.83 (s, 1H),8.45 (s, 1H), 7.80 (t, 1H), 7.18 (d, 1H), 4.32 (ddt 1H), 4.20 (dt, 1H),2.72-2.37 (m, 3H), 1.95-1.81 (m, 1H), 1.69-1.06 (m, 7H); MS(ES):344(M+H).

Where conjugate acceptors, such as were used in Example 737, Step 3 werenot commercially available, such compounds were generated according tothe procedure provided below for ethyl(2E)-3-(tetrahydrofuran-3-yl)acrylate (toward the preparation of Example733).

Preparation of ethyl (2E)-3-(tetrahydrofuran-3-yl)acrylate

Step A: Tetrahydrofuran-3-carbaldehyde

To a solution of Dess-Martin periodinane (3.37 g, 7.95 mmol) in DCM (20mL) was added tetrahydrofuran-3-ylmethanol (0.701 mL, 7.23 mmol). Thereaction was stirred at ambient temperature for 2 hours, and the solventwas then removed in vacuo. Flash column chromatography (using DCM aseluent) afforded the product as a clear oil, which was used withoutfurther purification.

¹H NMR (400 MHz, CDCl₃): δ□ 9.65 (d, 1H), 4.12-4.07 (m, 1H), 3.92-3.85(m, 2H), 3.80-3.73 (m, 1H), 3.10-3.02 (m, 1H), 2.26-2.10 (m, 2H).

Step B: Ethyl (2E)-3-(tetrahydrofuran-3-yl)acrylate

To a 0° C. mixture of sodium hydride (60% in mineral oil) (382 mg, 9.40mmol) in DMF (15.0 mL) (THF may also be used) was added triethylphosphonoacetate (1.72 mL, 8.68 mmol) dropwise. The resulting mixturewas warmed to room temperature and stirred for 30 minutes, then wasre-cooled to 0° C., at which time a solution oftetrahydrofuran-3-carbaldehyde (724 mg, 7.23 mmol) in DMF (4.0 mL) wasadded dropwise. The resulting mixture was stirred at this temperaturefor 1.5 hours, at which time the mixture was diluted with water and theproduct was extracted with ether. The combined extracts were washed withwater and brine, dried over sodium sulfate and the solvent removed invacuo. Flash column chromatography (eluting with a gradient from 0-40%ethyl acetate in hexanes) afforded the product (640 mg, 52%).

¹H NMR (400 MHz, CDCl₃): δ □6.87 (dd, 1H), 5.86 (dd, 1H), 3.96-3.88 (m,2H), 3.81 (dd, 1H), 3.53 (dd, 1H), 3.04-2.93 (m, 1H), 2.20-2.10 (m, 1H),2.03 (s, 3H), 1.79 (dq, 1H).

Example 736:4-[1-(1-Cyclopentyl-4,4-difluorobutyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidinetrifluoroacetate salt

4-[1-(1-Cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidinetrifluoroacetate salt (prepared as in Example 731) (20.0 mg, 0.041 mmol)was dissolved in methanol (3 mL), and a catalytic amount of 5% Pd on Cwas added. The mixture was stirred at room temperature for 2 hours,under an atmosphere of hydrogen provided by an affixed balloon. Themixture was filtered and purified via preparative-HPLC/MS (C18 elutingwith a gradient of H₂O and ACN containing 0.1% TFA) to afford product (4mg, 21%).

¹H NMR (400 MHz, d₆-DMSO): δ 12.74 (s, 1H), 8.88 (s, 1H), 8.85 (s, 1H),8.48 (s, 1H), 7.80 (t, 1H), 7.20 (dd, 1H), 6.05 (tt, 1H), 4.17 (dt, 1H),2.47-2.34 (m, 1H), 2.14-1.08 (m, 12H); MS(ES):346 (M+H).

Example 737:3-(1-Methylcyclopentyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitriletrifluoroacetate salt

Step 1. 1-Methylcyclopentanecarbaldehyde

To a solution of cyclopentanecarbaldehyde (1.00 mL, 9.36 mmol) in DCM(47 mL) at 0° C. was added solid potassium tert-butoxide (1.44 g, 12.2mmol) in one portion followed by methyl iodide (1.7 mL, 28 mmol) in oneportion. After 30 minutes at 0° C., the reaction mixture was allowed towarm to room temperature and stirred at that temperature for 16 hours.The mixture was poured into brine, and the layers were separated. Theorganic layer was dried over sodium sulfate, decanted and concentrated,and used without further purification in Step 2.

Step 2: (2Z)- and (2E)-3-(1-Methylcyclopentyl)acrylonitrile

To a solution of 1.0 M potassium tert-butoxide in THF (9.36 mL) at 0° C.was added a solution of diethyl cyanomethylphosphonate (1.59 mL, 9.81mmol) in THF (10 mL) dropwise. The cooling bath was removed and thereaction was warmed to room temperature followed by re-cooling to 0° C.,at which time a solution of 1-methylcyclopentanecarbaldehyde (1.0 g,generated in Step 1) in THF (2 mL) was added dropwise. The bath wasremoved and the reaction was stirred at ambient temperature for 3 hours.To the mixture was added water and ethyl ether. The aqueous layer wasfurther extracted with ethyl ether. The combined extracts were washedwith brine, dried over sodium sulfate, filtered and adsorbed onto silicagel in vacuo. Flash column chromatography (eluting with a gradient from0-10% ethyl acetate in hexanes) afforded product as a mixture withhexanes, which product was used without further purification in Step 3.

Step 3:3-(1-Methylcyclopentyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitriletrifluoroacetate salt

To a mixture of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(0.134 g, 0.426 mmol) in ACN (3 mL) was added a mixture of (2Z)- and(2E)-3-(1-methylcyclopentyl)acrylonitrile (0.12 g, 0.9 mmol) followed byDBU (0.13 mL, 0.90 mmol). The reaction was heated to 60° C. for 6 h. TheACN was removed in vacuo. Ethyl acetate was added, followed by 0.1 NHCl. The aqueous layer was extracted with three portions of ethylacetate. The combined organic extracts were washed with brine, driedover sodium sulfate, filtered and the solvent was evaporated. The crudematerial was deprotected by stirring with TFA (2 mL) in DCM (8 mL) for 2hours. The solvent and TFA were removed in vacuo. THF (8 mL) was used todissolve the residue, and 6.0 M sodium hydroxide in water (8 mL) wasadded. The reaction was stirred in this basic mixture for 2 hours. Ethylacetate was used to extract the product. The combined extracts weredried (Na₂SO₄) and the solvent was removed in vacuo. Purification viapreparative-HPLC/MS (C18 eluting with a gradient of H₂O and ACNcontaining 0.1% TFA) afforded product (44 mg, 24%).

¹H NMR (400 MHz, d₆-DMSO): δ 12.71 (s, 1H), 9.00 (s, 1H), 8.85 (s, 1H),8.51 (s, 1H), 7.81 (s, 1H), 7.18 (s, 1H), 4.72 (dd, 1H), 3.47 (dd, 1H),3.21 (dd, 1H), 1.74-1.51 (m, 6H), 1.44-1.32 (m, 1H), 1.09-1.00 (m, 1H),0.97 (s, 3H); MS(ES):321 (M+H).

Example 739:1-2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylcyclopropanecarbonitriletrifluoroacetate salt

Step1: 1-(Hydroxymethyl)cyclopropanecarbonitrile

Ethyl 1-cyanocyclopropanecarboxylate (801 mg, 5.76 mmol) in THF (12.0mL) was treated with lithium tetrahydroborate (251 mg, 11.5 mmol). Thesolution was heated to reflux for 1.5 hours. Upon cooling to roomtemperature, the reaction was quenched with water, and extracted withethyl acetate. The combined extracts were dried over MgSO₄, filtered andconcentrated to afford a clear oil, which was used without furtherpurification in the following step (482 mg, 86%).

¹H NMR (400 MHz, CDCl₃): δ□ 3.61 (s, 2H), 1.27 (dd, 2H), 0.98 (dd, 2H).

Step2: 1-Formylcyclopropanecarbonitrile

Dess-Martin periodinane (1.11 g, 2.62 mmol) was dissolved in DCM (12 mL)and 1-(hydroxymethyl)cyclopropanecarbonitrile (231 mg, 2.38 mmol) wasadded. The reaction was stirred at ambient temperature for one hour. Themixture was then purified by flash column chromatography (eluting with agradient from 0-80% ethyl acetate in hexanes) to afford the product (106mg, 46%).

¹H NMR (400 MHz, CDCl₃): δ□ 9.35 (s, 1H), 1.79-1.74 (m, 4H).

Step 3: 1-[(E)-2-Cyanovinyl]cyclopropanecarbonitrile

To a solution of 1.0 M potassium tert-butoxide in THF (1.12 mL) at 0° C.was added slowly dropwise a solution of diethyl cyanomethylphosphonate(210 mg, 1.2 mmol) in THF (2 mL). The cold bath was removed and thereaction was warmed to ambient temperature. The solution was thenre-cooled to 0° C. and a solution of 1-formylcyclopropanecarbonitrile(101 mg, 1.06 mmol) in THF (1.0 mL) was added dropwise. The cold bathwas removed and the reaction was stirred for 3 hours at ambienttemperature. The mixture was then diluted with ether and water, theether solution was separated, washed with brine, dried over sodiumsulfate, filtered and the solvent was removed in vacuo. Flash columnchromatography (eluting with a gradient from 0-60% ethyl ether inhexanes) afforded the product (24 mg, 19%).

¹H NMR (400 MHz, CDCl₃): δ□ 5.94 (d, 1H), 5.82 (d, 1H), 1.80 (dd, 2H),1.39 (dd, 2H).

Step 4: 1-2-Cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylcyclopropanecarbonitrile

To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(61.4 mg, 0.195 mmol) and 1-[(E)-2-cyanovinyl]cyclopropanecarbonitrile(23 mg, 0.19 mmol) in ACN (2 mL) was added DBU (58 uL, 0.39 mmol) andthe resulting mixture was stirred for 16 hours. The ACN was evaporated,and the residue was dissolved in ethyl acetate. This solution was washedwith 1.0 N HCl, water, and brine, and dried over sodium sulfate, and thesolvent removed in vacuo. Flash column chromatography (eluting with agradient from 0-80% ethyl acetate in hexanes) afforded the product (49mg, 58%).

¹H NMR (400 MHz, CDCl₃): δ□ 8.85 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H),7.43 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 3.54 (dd, 1H), 3.51 (dd, 1H),3.36 (dd, 1H), 1.62 (ddd, 1H), 1.45 (ddd, 1H), 1.34 (ddd, 1H), 1.25(ddd, 1H), 0.92 (t, 2H), −0.06 (s, 9H); MS(ES):434 (M+H).

Step 5:1-2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylcyclopropanecarbonitriletrifluoroacetate salt

1-2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylcyclopropanecarbonitrile(48 mg, 0.11 mmol) was stirred in a mixture of DCM (3 mL) and TFA (2 mL)for 3 hours. The solvents were removed in vacuo and the residue wasre-dissolved in THF (3 mL). 6N NaOH (2 mL) was added and the resultingmixture was stirred at ambient temperature for 3 hours. The crudereaction mixture was partitioned between ethyl acetate and water. Thelayers were separated and the organic layer was dried over sodiumsulfate and the solvent was removed in vacuo. Purification viapreparative-HPLC/MS (C18 eluting with a gradient of H₂O and ACNcontaining 0.1% TFA) afforded product (20 mg, 43%).

¹H NMR (400 MHz, d₆-DMSO): δ□ 12.74 (s, 1H), 8.99 (s, 1H), 8.88 (s, 1H),8.60 (s, 1H), 7.83 (t, 1H), 7.17 (dd, 1H), 4.55 (dd, 1H), 3.66 (dd, 1H),3.54 (dd, 1H), 1.55-1.30 (m, 4H); MS(ES):304 (M+H).

Example 740:N-[(1-2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl-cyclopentyl)methyl]benzamide

Step 1: Methyl 1-cyanocyclopentanecarboxylate

To a solution of acetic acid, cyano-, methyl ester (2.66 mL, 30.3 mmol)and 1,4-dibromobutane, (3.62 mL, 30.3 mmol) in acetone (50 mL) was addedpotassium carbonate (8.37 g, 60.6 mmol). The reaction was stirred atambient temperature for 16 hours. The reaction was filtered throughdiatomaceous earth and concentrated. The resulting residue waspartitioned between ether and saturated NH₄Cl solution, and the aqueouslayer was extracted with two further portions of ether. The combinedethereal extracts were washed with brine, and dried over sodium sulfate,then filtered and the solvent was removed in vacuo. Flash columnchromatography (eluting with a gradient from 0-30% ethyl acetate inhexanes) afforded the product (2.92 g, 63%).

¹H NMR (300 MHz, CDCl₃): δ□3.82 (s, 3H), 2.30-2.21 (m, 4H), 1.93-1.82(m, 4H).

Step 2: Methyl1-[(tert-butoxycarbonyl)amino]methylcyclopentanecarboxylate

To a solution of methyl 1-cyanocyclopentanecarboxylate (1.26 g, 8.22mmol) in methanol (100 mL) was added cobalt dichloride (2.1 g, 16.0mmol). The purple mixture was cooled in an ice-water bath. Sodiumtetrahydroborate (3.11 g, 82.2 mmol) was added portionwise with caution(exothermic) to provide a black mixture. Upon complete addition, coolingwas discontinued and the reaction was stirred for 40 minutes undernitrogen and the reaction was quenched by the careful addition of 1N HCl(700 ml). The methanol was removed in vacuo, and the solution was thenmade alkaline (pH ˜9) by the addition of concentrated NH₄OH(aq). Themixture was extracted with DCM (6 times), and the combined DCM extractswere dried over sodium sulfate and concentrated to afford the crudeproduct as a light yellow oil. To this crude amine in DCM (50 ml) wasadded di-tert-butyldicarbonate (1.31 g, 6.01 mmol) and the reaction wasstirred at 25° C. for 30 minutes. The reaction was diluted with waterand extracted with ethyl acetate three times. The combined extracts weredried over sodium sulfate, filtered, and the solvent removed in vacuo.The crude residue was purified by flash column chromatography to yieldthe desired product (1.5 g, 71%).

¹H NMR (300 MHz, CDCl₃): δ□ 5.03 (s, 1H), 3.69 (s, 3H), 3.26 (d, 2H),2.02-1.33 (m, 17H).

Step 3: tert-Butyl [1-(hydroxymethyl)cyclopentyl]methylcarbamate

To a solution of methyl1-[(tert-butoxycarbonyl)amino]methylcyclopentanecarboxylate (1.50 g,5.83 mmol) in THF (25.0 mL) at −78° C. was added dropwise 1.0 Mdiisobutylaluminum hydride in DCM (17.5 mL). The reaction was stirredfor 2 hours with slow warming to −10° C. A saturated solution of K/Natartrate was added, followed by ether. This mixture was stirred for 30minutes at ambient temperature and the organic layer was separated andwashed with water, and brine. The organic layer was then dried oversodium sulfate, and the solvent was removed in vacuo to afford theproduct (1.03 g, 77%). ¹H NMR (300 MHz, CDCl₃): δ □4.90 (br s, 1H), 3.27(s, 2H), 3.06 (d, 2H), 1.5-1.17 (m, 8H), 1.44 (s, 9H).

Step 4: tert-Butyl [(1-formylcyclopentyl)methyl]carbamate

To a solution of oxalyl chloride (456 μL, 5.38 mmol) in DCM (30.0 mL) at−78° C. was added DMSO (637 μL, 8.97 mmol) and the resulting mixture wasstirred for 5 minutes. tert-Butyl[1-(hydroxymethyl)cyclopentyl]methylcarbamate (1.03 g, 4.48 mmol) in DCM(10.0 mL) was added and the resulting mixture was stirred for 30 minutesat −78° C. TEA (2.50 mL, 17.9 mmol) was added and the resulting mixturewas allowed to warm to ambient temperature over 30 minutes. Water wasadded. The organic phase was washed sequentially with 0.1 N HCl, water,saturated sodium bicarbonate solution, and brine, and then dried oversodium sulfate and the solvent was removed in vacuo to afford theproduct (957 mg, 94%). ¹H NMR (300 MHz, CDCl₃): δ□ 9.39 (s, 1H), 4.94(br s, 1H), 3.25 (d, 2H), 1.89-1.46 (m, 8H), 1.41 (s, 9H).

Step 5: tert-Butyl (1-[(E)-2-cyanovinyl]cyclopentylmethyl)carbamate andtert-butyl (1-[(Z)-2-cyanovinyl]cyclopentylmethyl) carbamate

To a solution of 1.0 M potassium tert-butoxide in THF (4.4 mL) at 0° C.was added a solution of diethyl cyanomethylphosphonate (820 mg, 4.6mmol) in THF (6.0 mL) dropwise. The cold bath was removed and thereaction was warmed to ambient temperature. The mixture was thenre-cooled to 0° C. and a solution of tert-butyl[(1-formylcyclopentyl)methyl]carbamate (952 mg, 4.19 mmol) in THF (4.0mL) was added dropwise. The reaction was allowed to warm to ambienttemperature and the warmed mixture was stir for 16 hours. The reactionmixture was then diluted with ether and water. The organic layer wasseparated and washed sequentially with water and brine, then dried oversodium sulfate, then filtered, and the solvent was removed in vacuo toafford the product (1.05 g, 99%) as a mixture of (E) and (Z) isomers.

¹H NMR (300 MHz, CDCl₃): δ 6.71 (d, 1H, E), 6.46 (d, 1H, Z), 5.36 (d,1H, Z), 5.36 (d, 1H, E), 4.70 (br s, 1H, Z), 4.51 (br s, 1H, E), 3.25(d, 2H, Z), 3.18 (d, 2H, E), 1.88-1.48 (m, 8H (E) and 8H (Z)), 1.43 (s,9H (E) and 9H (Z)); MS(ES):151 (M+H-Boc).

Step 6: tert-Butyl[(1-2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylcyclopentyl)methyl]carbamate

To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(355 mg, 1.12 mmol) and tert-butyl(1-[(E)-2-cyanovinyl]cyclopentylmethyl)carbamate and tert-butyl(1-[(Z)-2-cyanovinyl]cyclopentylmethyl)carbamate as a mixture of isomers(329 mg, 1.31 mmol) in ACN (10 mL) was added DBU (0.168 mL, 1.12 mmol).The resulting mixture was stirred at ambient temperature for 3 hoursfollowed by heating to 60° C. for 2.5 hours. The ACN was removed invacuo and the resulting residue was purified by flash columnchromatography (eluting with 0-55% ethyl acetate in hexanes) to affordthe product (350 mg, 55%).

¹H NMR (300 MHz, CDCl₃): δ□ 8.85 (s, 1H), 8.37 (br s, 1H), 8.34 (s, 1H),7.41 (d, 1H), 6.82 (d, 1H), 5.68 (s, 2H), 5.37 (br s, 1H), 4.52 (dd,1H), 3.54 (t, 2H), 3.40 (dd, 1H), 3.23 (dd, 1H), 3.08 (d, 1H), 2.90 (dd,1H), 1.84-1.47 (m, 8H), 1.45 (s, 9H), 0.92 (t, 2H), −0.06 (s, 9H);MS(ES):566 (M+H).

Step 7:N-[(1-2-Cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylcyclopentyl)-methyl]benzamide

A solution of tert-butyl[(1-2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylcyclopentyl)methyl]carbamate(175 mg, 0.309 mmol) in DCM (5 mL) and TFA (5 mL) was stirred for 3hours and the solvents were then removed in vacuo. The resulting residuewas stirred in a mixture of THF (3 mL) and 6N NaOH (3 mL) for 3 hours.The THF was removed in vacuo, and water (10 mL) was added. The mixturewas extracted with several portions of DCM containing 15% isopropanol.The combined extracts were dried over sodium sulfate and the solventswere removed in vacuo to afford the product, which was used withoutfurther purification. MS(ES):336 (M+H).

To a solution of3-[1-(aminomethyl)cyclopentyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(31 mg, 0.060 mmol) and benzoyl chloride (7.0 μL, 0.060 mol) in DCM (1.0mL), was added TEA (17 μL, 0.12 mmol). After 15 minutes, the solvent wasremoved in vacuo and the mixture was purified via preparative-HPLC/MS(C18 eluting first with a gradient of H₂O and ACN containing 0.1% TFA,followed by chromatographic purification, eluting with a gradient of H₂Oand ACN containing 0.15% NH₄OH) to afford the product (7 mg, 27%).

¹H NMR (400 MHz, d₆-DMSO): δ□12.12 (s, 1H), 8.95 (s, 1H), 8.68 (s, 1H),8.55 (s, 1H), 8.41 (s, 1H), 7.92-7.87 (m, 2H), 7.60 (d, 1H), 7.59-7.48(m, 3H), 7.02 (d, 1H), 4.83 (dd, 1H), 3.52-3.45 (m, 2H), 3.42 (dd, 1H),3.27 (dd, 1H), 2.06-1.95 (m, 1H), 1.68-1.12 (m, 7H); MS(ES):440 (M+H).

Example 741:3-1-[(Benzyloxy)methyl]cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitriletrifluoroacetate salt

Step 1: 1-(Hydroxymethyl)cyclopentanecarbonitrile

A mixture of methyl 1-cyanocyclopentanecarboxylate (prepared in Example740, Step 1) (500 mg, 3.0 mmol) in THF (7 mL) was treated with lithiumtetrahydroborate (100 mg, 6.0 mmol). The resulting solution was heatedto reflux for 3 hours, then stirred at ambient temperature for 16 hours.The mixture was quenched by the addition of water, and was extractedwith ethyl acetate. The combined organic extracts were dried overNa₂SO₄, then filtered and the solvent was removed in vacuo to afford theproduct (387 mg, 95%). ¹H NMR (300 MHz, CDCl₃): δ□3.62 (s, 2H),2.39-1.60 (m, 8H).

Step 2: 1-[(Benzyloxy)methyl]cyclopentanecarbonitrile

To a solution of 1-(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineraloil, 0.101 g, 2.52 mol). The resulting mixture was stirred for 20minutes, followed by the addition of benzyl bromide (0.28 mL, 2.4 mmol).The reaction was stirred at ambient temperature for 64 hours. Additionalsodium hydride (60% dispersion in mineral oil, 0.060 g, 1.5 mmol) andbenzyl bromide (0.18 mL, 1.5 mmol) were added and the reaction wasstirred for an additional 30 minutes. Water was then added to themixture, followed by brine, and the aqueous layer was extracted withethyl acetate. The extracts were combined and dried over sodium sulfate,and the solvent was then removed in vacuo. To the resulting residue wasadded water. The product was isolated by extraction with diethyl ether.The ethereal extracts were dried over sodium sulfate, and the solventwas evaporated. Flash column chromatography (eluting with a gradientfrom 0-30% ethyl acetate in hexanes) afforded product (330 mg, 64%).

¹H NMR (300 MHz, CDCl₃): δ□7.40-7.27 (m, 5H), 4.62 (s, 2H), 3.44 (s,2H), 2.18-2.03 (m, 2H), 1.90-1.62 (m, 6H).

Step 3: 1-[(Benzyloxy)methyl]cyclopentanecarbaldehyde

To a mixture containing 1-[(benzyloxy)methyl]cyclopentanecarbonitrile(0.16 g, 0.75 mmol) in toluene (5 mL) at 0° C. was added 1.0 Mdiisobutylaluminum hydride in hexanes (0.8 mL). The reaction was stirredat 0° C. for 1.5 hours, during which time the starting nitrile wasconsumed. The reaction was cooled to −78° C. and quenched by theaddition of methanol. The mixture was warmed to ambient temperature and3 N HCl was added. Following stirring for 45 minutes, solid NaCl wasadded, and the mixture was extracted with three portions of ethylacetate. The combined extracts were dried (Na₂SO₄), and filtered, andthe solvent was removed in vacuo. Flash column chromatography of theresulting residue (eluting with a gradient from 0-30% ethyl acetate inhexanes) afforded the product (20 mg, 12%).

¹H NMR (300 MHz, CDCl₃): δ□ 9.60 (s, 1H), 7.38-7.26 (m, 5H), 4.52 (s,2H), 3.54 (s, 2H), 2.00-1.89 (m, 2H), 1.66-1.46 (m, 6H).

Step 4: (2E)- and (2Z)-3-1-[(Benzyloxy)methyl]cyclopentylacrylonitrile

To a stirred solution of diethyl cyanomethylphosphonate (18 μL, 0.11mmol) in THF (1 mL) was added 1.0 M potassium tert-butoxide in THF (0.10mL). The resulting mixture was stirred 30 minutes, after which asolution of 1-[(benzyloxy)methyl]cyclopentanecarbaldehyde (0.020 g,0.092 mmol) in THF (1 mL) was added. The resulting mixture was stirredfor 16 hours. Water was then added to the reaction and the resultingmixture was extracted with three portions of ethyl ether. The combinedextracts were washed with brine, then dried over sodium sulfate,decanted from the sodium sulfate, and the solvent was removed in vacuoto afford the product, which was used without further purification inthe subsequent conjugate addition step.

¹H NMR (400 MHz, CDCl₃): δ □7.37-7.27 (m, 5H), 6.80 (d, 1H (E)), 6.59(d, 1H (Z)), 5.34 (d, 1H (E)), 5.33 (d, 1H (Z)), 4.53 (s, 2H (Z)), 4.50(s, 2H (E)), 3.45 (s, 2H (Z)), 3.31 (s, 2H (E)), 1.80-1.55 (m, 8H);MS(ES)=242 (M+H).

Step 5:3-1-[(Benzyloxy)methyl]cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitriletrifluoroacetate salt

To a mixture of (2E)- and(2Z)-3-1-[(benzyloxy)methyl]cyclopentylacrylonitrile (generated in Step4) and4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(0.037 g, 0.12 mmol) in ACN (1.5 mL) was added DBU (18 μL, 0.12 mmol).The resulting mixture was stirred at ambient temperature for 3 hours,and then was heated to 60° C. for 28 hours. The reaction mixture wasdiluted with diethyl ether and 0.1 N HCl. The layers were separated andthe aqueous layer was extracted with ethyl acetate. The ethyl acetateextract was washed with brine, dried over sodium sulfate, decanted, andthe solvent was removed in vacuo. The resulting residue was dissolved inDCM (3 mL) and TFA (0.75 mL), and this solution was stirred for 3 hours.The solvents were removed in vacuo, and the resulting residue wasdissolved in THF (5 mL) and 6.0 M sodium hydroxide in water (3 mL) andstirred for 2 hours. The reaction mixture was extracted with threeportions of ethyl acetate. The combined extracts were washed with brine,dried over sodium sulfate, decanted, and the solvent was removed invacuo. The crude mixture was purified by preparative-HPLC/MS (C18eluting with a gradient of H₂O and ACN containing 0.1% TFA) andlyophilized to afford the desired product (10 mg, 20% over the twosteps).

¹H NMR (400 MHz, d₆-DMSO): δ□12.71 (br s, 1H), 8.99 (s, 1H), 8.86 (s,1H), 8.52 (s, 1H), 7.80 (s, 1H), 7.38-7.23 (m, 5H), 7.19-7.16 (m, 1H),4.92 (dd, 1H), 4.50 (d, 1H), 4.44 (d, 1H), 3.49 (dd, 1H), 3.35 (d, 1H),3.23 (dd, 1H), 3.05 (d, 1H), 1.92-1.82 (m, 1H), 1.66-1.27 (m, 7H);MS(ES):427 (M+H).

Example 742:3-[1-(Methylsulfonyl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitriletrifluoroacetate salt

Step 1: Benzyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate

To a solution of 1-[(benzyloxy)carbonyl]pyrrolidine-3-carboxylic acid(1.0 g, 4.0 mmol) in THF (37 mL) at 0° C. was added dropwise a solutionof 1.0 M borane in THF (16.4 mL). The reaction was allowed to warm toroom temperature and stir for 16 hours. The mixture was cooled to 0° C.and 10% HCl (50 mL) was added. After the addition, the mixture wasextracted with DCM, and the extract was washed sequentially withsaturated NaHCO₃ solution and brine, then dried over sodium sulfate,filtered and the solvent was removed in vacuo. The product was usedwithout further purification in the subsequent oxidation step.

¹H NMR (300 MHz, CDCl₃): δ□ 7.39-7.26 (m, 5H), 5.11 (s, 2H), 3.61-3.31(m, 5H), 3.18 (dt, 1H), 2.75 (br s, 0.45H), 2.59 (br s, 0.45H),2.49-2.31 (m, 1H), 2.19 (br s, 0.1H), 2.05-1.89 (m, 1H), 1.77-1.58 (m,1H); MS(ES):236 (M+H).

Step 2: Benzyl 3-formylpyrrolidine-1-carboxylate

DMSO (597 μL, 8.42 mmol) was added to a solution of oxalyl chloride (427μL, 5.05 mmol) in DCM (25 mL) at −78° C. After 5 minutes, benzyl3-(hydroxymethyl)pyrrolidine-1-carboxylate (generated in Step 1) wasadded. The reaction was continued for 30 minutes at −78° C. TEA (2.3 mL,17 mmol) was then added. The resulting mixture was then allowed to warmto room temperature over the course of 30 minutes. Water was then added.The layers were separated and the organic phase was washed sequentiallywith 0.1 N HCl, water, saturated NaHCO₃, and brine. The organic phasewas then dried over sodium sulfate and the solvent was removed in vacuoto afford the product (0.82 g, 88% over two steps).

¹H NMR (300 MHz, CDCl₃): δ□ 9.68 (d, 1H), 7.38-7.28 (m, 5H), 5.13 (s,2H), 3.79 (dd, 1H), 3.65-3.35 (m, 3H), 3.11-2.99 (m, 1H), 2.32-2.04 (m,2H).

Step 3: Benzyl 3-[(E)-2-cyanovinyl]pyrrolidine-1-carboxylate and benzyl3-[(Z)-2-cyanovinyl]-pyrrolidine-1-carboxylate

To a solution of 1.0 M potassium tert-butoxide in THF (4.40 mL) at 0° C.was added a solution of diethyl cyanomethylphosphonate (820 mg, 4.6mmol) in THF (6.0 mL) dropwise. The cold bath was removed and thereaction was warmed to room temperature and stirred for 15 minutes. Themixture was cooled to 0° C. and a solution of benzyl3-formylpyrrolidine-1-carboxylate (0.82 g, 2.3 mmol) in THF (4.00 mL)was added dropwise. Cooling was discontinued and the reaction stirredfor 16 hours at ambient temperature. The mixture was diluted with etherand water, the layers were separated and the organic layer was washedwith water, followed by brine, and then dried over sodium sulfate,filtered and the solvent was removed in vacuo. The resulting residue waspurified by flash column chromatography (eluting with a gradient from0-35% ethyl acetate in hexanes) to afford the product as a mixture of Eand Z isomers (246 mg, 42%).

¹H NMR (300 MHz, CDCl₃): δ 7.41-7.27 (m, 5H), 6.70-6.58 (m, 0.3H (E)),6.38 (dt, 0.7H (Z)), 5.50-5.30 (m, 1H), 5.14 (s, 2H), 3.79-3.11 (m, 5H),2.27-2.06 (m, 1H), 1.90-1.70 (m, 1H); MS(ES):279 (M+Na).

Step 4: Benzyl3-2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylpyrrolidine-1-carboxylate

To a mixture of benzyl 3-[(E)-2-cyanovinyl]pyrrolidine-1-carboxylate andbenzyl 3-[(Z)-2-cyanovinyl]pyrrolidine-1-carboxylate (241 mg, 0.940mmol) and DBU (234 μL, 1.57 mmol) in ACN (13 mL) was added4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(250 mg, 0.78 mmol). The mixture was stirred at ambient temperature for3 hours. The solvent was removed in vacuo. The resulting residue wasdissolved in ethyl acetate, and the organic layer was washedsequentially with 1N HCl, water, saturated NaHCO₃, and brine. The washedsolution was dried over sodium sulfate and the solvent was removed invacuo. Purification via flash column chromatography (eluting with agradient of 0-100% [5% MeOH/DCM] in hexanes) afforded the produce as amixture of diastereomers (400 mg, 89%).

¹H NMR (400 MHz, CDCl₃ a mixture of diastereomers): □δ □8.85 (s, 1H),8.35-8.28 (m, 2H), 7.42-7.25 (m, 6H), 6.80-6.76 (m, 1H), 5.69-5.66 (m,2H), 5.15-5.04 (m, 2H), 4.46-4.32 (m, 1H), 3.84-3.84 (m, 6H), 3.54 (t,2H), 2.26-2.13 (m, 1H), 1.84-1.54 (m, 2H), 0.95-0.89 (m, 2H), −0.06 (s,9H); MS(ES):572 (M+H).

Step 5.3-Pyrrolidin-3-yl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile

Benzyl3-2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylpyrrolidine-1-carboxylate(161 mg, 0.282 mmol) was dissolved in methanol (5 mL), and a catalyticamount of 5% Pd—C was added. The suspension was stirred at ambienttemperature for 1 hour under an atmosphere of hydrogen provided by aballoon. A catalytic amount of 10% Pd—C was then added, and the reactionstirred for 2 hours under an atmosphere of hydrogen provided by aballoon. The mixture was then filtered, and purified viapreparative-HPLC/MS (C18 eluting with a gradient of H₂O and ACNcontaining 0.15% NH₄OH) to afford the product as a mixture ofdiastereomers (57 mg, 46%).

¹H NMR (400 MHz, CDCl₃, a mixture of diastereomers): δ 8.84 (s, 1H),8.34-8.32 (m, 2H), 7.40 (d, 1H), 6.81-6.78 (m, 1H), 5.67 (s, 2H), 4.38(dt, 1H), 3.54 (t, 2H), 3.30-1.38 (m, 9H), 0.92 (t, 2H), −0.06 (s, 9H);MS(ES):438 (M+H).

Step 6:3-[1-(Methylsulfonyl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]propanenitriletrifluoroacetate salt

To a solution of3-pyrrolidin-3-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidinyl)1H-pyrazol-1-yl]propanenitrile(25 mg, 0.057 mmol) and TEA (10 μL, 0.074 mmol) in DCM (1.0 mL) at 0° C.was added methanesulfonyl chloride (6 μL, 0.074 mmol). The reaction wasallowed to reach ambient temperature and stir for 16 hours. Half of thesolvent was removed in vacuo and TFA (1 mL) was added to the vial. Afterstirring for 1 hour at room temperature, the solvents were removed invacuo and the resulting residue reconstituted in THF (0.5 mL). To thiswas added 6 N NaOH (1 mL) and this solution was stirred for 2 hours. Thereaction mixture was extracted with five portions of ethyl acetate. Thecombined extracts were dried (Na₂SO₄), decanted and concentrated.Preparative-HPLC/MS (C18 eluting with a gradient of H₂O and ACNcontaining 0.1% TFA) was used to afford the product (16 mg, 57%).

¹H NMR (400 MHz, d₆-DMSO, a mixture of diastereomers): δ 12.69 (s, 1H),8.98 (s, 0.5H), 8.95 (s, 0.5H), 8.84 (s, 1H), 8.53-8.51 (m, 1H),7.80-7.77 (m, 1H), 7.16-7.13 (m, 1H), 4.86-4.75 (m, 1H), 3.55-3.48 (m,1H), 3.42-3.08 (m, 4H), 2.99-2.91 (m, 1H), 2.90 (s, 1.5H), 2.85 (s,1.5H), 2.16-2.07 (m, 1H), 1.82-1.70 (m, 1H), 1.64-1.48 (m, 1H);MS(ES):386 (M+H).

Example 743:N′-Cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboximidamide

Step 1: tert-Butyl 4-(cyanomethylene)piperidine-1-carboxylate

To a solution of 1.0 M potassium tert-butoxide in THF (10.1 mL) at 0° C.was added a solution of diethyl cyanomethylphosphonate (1.66 mL, 0.0102mol) in THF (20 mL) dropwise. The reaction was held for 10 min, thenadded to a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.00 g,0.0100 mol) in THF (30 mL) stirring at 0° C. under an atmosphere ofnitrogen. After complete addition, the cold bath was removed and thereaction was allowed to stir 1.0 h at 20° C. LCMS analysis showed thedesired product and no remaining starting material. HPLC showed theproduct UV_(max) at 200 & 230 nm. Water and EtOAc were added to thereaction mixture. The phases were separated, and the aqueous phase wasextracted with EtOAc. The combined organic phase was washed with water,then saturated NaCl, then dried over Na₂SO₄, and concentrated to drynessto provide 2.5 g of the product as a yellow oil. TLC (25% EtOAc/hexane)R_(f) 0.22. The product was purified by automatic flash chromatographyon silica gel. Used a 40 g column; flow 40 mL/min; [A=hexane] [B=EtOAc].A, 4 min; Gradient to 20% B in 30 min. Collected 44 mL fractions. Theproduct eluted in 21-27 min. The fractions were concentrated to yield0.67 g of a white solid. ¹H NMR (CDCl₃) δ 5.19 (s, 1H); 3.51 (m, 4H);2.56 (t, 2H); 2.33 (t, 2H); 1.50 (s, 9H). MS(ES) 245 (M+Na, weak; basepeak M+H-56=167).

Step 2: tert-Butyl4-(cyanomethyl)-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate

4-(1H-Pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(0.840 g, 2.66 mmol) was slurried in a mixture of ACN (20 mL) and DBU(398 μL, 2.66 mmol), and tert-butyl4-(cyanomethylene)piperidine-1-carboxylate (0.651 g, 2.93 mmol) wasadded. The pyrazole did not dissolve at 20° C., but a solution wasformed when the mixture was heated to 40° C. for 1 h. LCMS and HPLCanalyses showed about 20% conversion to product. The mixture was stirredat 40-45° C. overnight. HPLC showed 60 area % product. The ACN wasremoved by retory evaporator at 20° C. To the resulting residue wasadded saturated NaHCO₃ and EtOAc. The organic layer was shaken with moreaqueous saturated NaHCO₃, then dried (Na₂SO₄) and rotovaped to give 1.6g of a brown oil residue. TLC (60% EtOAc/hexane): product R_(f)=0.25.The product was purified by automatic flash chromatography on silicagel, using a 40 g column, at a flow of 40 mL/min; [A=hexane] [B=EtOAc].A, 3 min; Gradient to 100% B in 50 min. Collected 44 mL fractions. Theproduct eluted in 24-29 min; the pyrazole in 39-46 min; and the olefinin 13-15 min. Solvent was removed in vacuo for the appropriate fractionsto give 0.27 g olefin; 0.30 g pyrazole; and a yield of 0.67 g of theproduct, all of which were isolated as white solids. ¹H NMR (CDCl₃) δ8.84 (s, 1H); 8.42 (s, 1H); 8.33 (s, 1H); 7.40 (d, 1H); 6.79 (d, 1H);5.67 (s, 2H); 3.94 (m, 2H); 3.54 (m, 2H); 3.07 (m, 2H); 2.90 (s, 2H);2.72 (m, 2H); 2.08 (m, 2H); 1.45 (s, 9H); 0.91 (m, 2H); −0.06 (s, 9H).MS(ES) 538 (M+H).

Step 3:4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidin-4-ylacetonitrile

tert-Butyl4-(cyanomethyl)-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(0.670 g, 1.24 mmol) was dissolved in TFA (5.0 mL, 65 mmol) and wasstirred for 1.3 h. LCMS showed conversion to the hydroxymethylintermediate, M+H 338. The solution was concentrated to remove the TFA.Methanol was added to the resulting residue, and the resulting mixturewas concentrated. The resulting residue was dissolved in methanol (10mL) and 15.0 M ammonium hydroxide in water (1.66 mL) was added. Theresulting solution was stirred for 2 h. LCMS and HPLC analyses showedcomplete deprotection. The mixture was concentrated. Toluene was addedto the resulting residue and the resulting mixture was concentrated toprovide a white semisolid. Most of this intermediate product was usedfor the next step. The rest was purified by prep HPLC using a 30 mm×100mm C18 column; 8% ACN-H₂O (0.1% NH₄OH), 1.0 min, to 27% at 6 min; 60mL/min; detector set at m/z 308; retention time, 5.4 min. Tubescontaining pure product were combined and freeze dried to give 13.6 mgof the product.

¹H NMR (d₆-DMSO) δ 12.07 (s, 1H); 8.68 (s, 1H); 8.62 (s, 1H); 8.36 (s,1H); 7.54 (d, 1H); 7.00 (d, 1H); 3.16 (s, 2H); 2.87 (m, 2H); 2.55 (m,4H); 1.94 (m, 2H). MS(ES) 308 (M+H).

Step 4: MethylN-cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-piperidine-1-carbimidothioate

4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidin-4-ylacetonitrile(361 mg, 1.17 mmol) and N-cyano-S,S′-dimethyldithioimido carbonate (344mg, 2.35 mmol) were dissolved in isopropyl alcohol (2.5 mL) and DMSO(2.5 mL) at 20° C. After 16 h reaction time, LCMS analysis showed thepresence of some product, M+H 406; of the reagent, M+H 147; and of thepiperidine, M+H 308. HPLC analysis showed about 2% reaction. The HPLCmethod was: Zorbax SB C18, 5 μm, 15 cm, 35° C., flow 1.2 mL/min, 5%ACN-H₂O (0.05% TFA), 1.5 min, to 100% ACN in 15.0 min; detector set at324, 225, and 265 nm. The retention time of the starting material was4.9 min (UV max 224, 262, 292, & 325 nm); of the product, 6.5 min (UVmax 226, 262, 290, & 324 nm); and of the reagent, 7.7 min (UV max 265nm). To the product was added TEA (327 μL, 2.35 mmol), and the resultingmixture was stirred at RT. After stirring for 3 h, HPLC and LCMSanalyses showed 60% reaction. The product and the unreacted piperidinewere isolated by prep HPLC using a 30 mm×100 mm C18 column; 5% ACN-H₂O(0.1% TFA), 1.0 min, to 35% at 6 min; 60 mL/min; detector set at 326 nm.The retention time for the product was 5.9 min; and for the startingpiperidine was 3.5-4.3 min. The product was freeze dried to yield 301 mgof a white solid TFA salt. ¹H NMR (d₆-DMSO) δ 12.85 (s, 1H); 9.01 (s,1H); 8.90 (s, 1H); 8.59 (s, 1H); 7.85 (m, 1H); 7.30 (m, 1H); 4.23 (m,2H); 3.35 (m, 2H); 3.30 (s, 2H); 2.78 (m, 2H); 2.68 (s, 3H); 2.16 (m,2H). MS(ES) 406 (M+H).

Step 5:N′-Cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboximidamide

MethylN-cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-piperidine-1-carbimidothioate(41.3 mg, 0.102 mmol) (53 mg TFA salt) was dissolved in 2.0 M ammonia inisopropyl alcohol (4.00 mL). The resulting mixture was heated to 100° C.for 1 h in a microwave reactor. Analysis by HPLC and LCMS showed 60%reaction to give the expected M+H 375 (50 area %). To this mixture wasadded 2 mL of 7 N NH₃/MeOH. The resulting mixture was heated at 120° C.for one hour. HPLC and LCMS analyses showed no remaining startingmaterial. The reaction mixture was concentrated on a rotory evaporator.The product was isolated by prep HPLCMS using a 30 mm×100 mm C18 column,eluting with a solvent gradient; 10% ACN-H₂O (0.1% TFA), 1.5 min, to 30%at 6 min; 60 mL/min; detector set at m/z 375; retention time, 4.7 min.The eluate was freeze-dried to yield 11.7 mg of the product TFA salt asa white solid. ¹H NMR (d₆-DMSO) δ 12.69 (s, 1H, NH); 8.92 (s, 1H); 8.81(s, 1H); 8.51 (s, 1H); 7.75 (m, 1H); 7.22 (m, 1H); 7.18 (s, 2H, NH2);3.84 (m, 2H); 3.23 (s, 2H); 2.99 (m, 2H); 2.60 (m, 2H); 1.97 (m, 2H).MS(ES) 375 (M+H).

Example 744:4-1-[2,2,2-Trifluoro-1-(1H-imidazol-2-ylmethyl)ethyl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrimidine

Step1:(3R)-4,4,4-Trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanal

To a −70° C. solution of(3R)-4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile(1.06 g, 0.00243 mol) (see, Example 93, Step1) in DCM (10 mL, 0.2 mol)was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL). Theresulting mixture was stirred for 3 h and allowed to warm during thistime interval from −70 to −25° C., after which the reaction was cooledback at −70° C. Methanol (1.5 mL, 0.037 mol) was added, followed by 2.0M HCl in water (15 mL). Insoluble material was then filtered from thereaction mixture. The organic filtrate was washed sequentially with: 2.0M HCl in water, water and saturated aqueous NaCl. The washed organicphase was dried over sodium sulfate and was concentrated using a rotoryevaporator to give 0.58 g of the crude product as a pale yellowfoam/solid. The crude product was chromatographed with 0-80% ethylacetate/hexanes to give the purified product (0.9 g) as a pale orangeoil (47% yield).

¹H NMR (400 MHz, CDCl₃): δ 9.85 (1H, s); 8.95 (1H, s); 8.5 (1H, s); 8.4(1H, s); 7.5 (1H, d); 6.85 (1H, d); 5.75 (2H, s); 5.5 (1H, m); 4.0 (1H,dd); 3.6 (2H, t); 3.3 (1H, dd); 1.99 (2H, t); 0.0 (9H, s). MS (M+H):440.

Step2:4-1-[2,2,2-Trifluoro-1-(1H-imidazol-2-ylmethyl)ethyl]-1H-pyrazol-4-yl-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine

A solution of4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]butanal(0.138 g, 0.000314 mol), 7.0 M ammonia in methanol (1 mL), ethanedial(0.5 mL, 0.004 mol) and acetic acid (20 uL, 0.0004 mol) in methanol (2mL, 0.05 mol) was microwaved on 100 watts, at 80° C. for 60 minutes.Following the microwave reaction, ethyl acetate/water was added. Theorganic phase was separated and washed with saturated NaHCO₃ andsaturated NaCl. The washed organic phase was dried and concentrated(rotory evaporator) to give 196 mg of the crude product as an orangeglass. The crude product was purified by chromatography with 0-100%ethyl acetate/hexanes to give 57 mg of purified product as an off-whitesolid (38% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.91 (1H, s); 8.4 (1H, s); 8.2 (1H, s); 7.5(1H, d); 7.0 (2H, s); 6.83 (1H, d); 5.75 (2H, s); 5.62 (1H, m); 4.15(1H, dd); 3.8 (1H, dd); 3.6 (2H, t); 1.99 (2H, t); 0.0 (9H, s). MS(M+H): 478.

Step3:4-1-[2,2,2-Trifluoro-1-(1H-imidazol-2-ylmethyl)ethyl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]-pyrimidine

A solution of4-1-[2,2,2-trifluoro-1-(1H-imidazol-2-ylmethyl)ethyl]-1H-pyrazol-4-yl-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine(0.055 g, 0.12 mmol) in 1,2-dichloroethane (1 mL, 10 mmol) and TFA (0.5mL, 6 mmol) was stirred overnight. The reaction was concentrated toprovide an orange oil. The oil was stirred in methanol (1 mL, 20 mmol)and 8.0 M ammonium hydroxide in water (1 mL) for 4 h. This mixture wasthen concentrated to provide a crude product as an orange glass/solid.The crude product was purified by Prep HPLC (pH10) to give 28 mg ofpurified product as a colorless glass, which was triturated with2-methoxy-2-methylpropane (1 mL, 8 mmol), and then filtered and washedto provide 15 mg of the product as a white solid (38% yield) which thenwas dried rt-50° C. for 3 h.

¹H NMR (400 MHz, DMSO): δ 12.13 (1H, s); 11.89 (1H, s); 8.65 (1H, s);8.37 (1H, s); 7.6 (1H, d); 6.95 (1H, d); 6.92 (1H, d); 5.91 (1H, m);3.78 (1H, dd); 3.47 (H, dd). MS (M+H): 348.

Example 745:4-(1-(1R)-2,2,2-Trifluoro-1-[(4-methyl-1,3-thiazol-2-yl)methyl]ethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

Step 1:(3R)-4,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-yl]butanethioamide

A suspension of phosphorus pentasulfide (0.46 g, 1.0 mmol) in ethanol(0.5 mL, 8 mmol) was stirred for 1 h.(3R)-4,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile(0.15 g, 0.50 mmol) (see, Example 93) was added and the resultingmixture was heated at 80° C. in a sealed vial for 0.5 h, during whichreaction the mixture became a yellow solution. The reaction was heatedovernight. The reaction was then cooled to rt. Water (1 g, 60 mmol) andethyl acetate were added to the mixture. The organic phase was separatedand washed with saturated NaHCO₃ and saturated aqueous NaCl. The washedorganic phase was then dried and concentrated to give 387 mg of a crudeproduct as a white glass/oil. The crude product was chromatographed with0-10% MeOH/DCM, 0-1% NH₄OH to give 0.13 g of the purified product as awhite solid (76% yield).

¹H NMR (400 MHz, CDCl₃): δ 8.7 (1H, s); 8.5 (1H, s); 8.3 (1H, s); 7.4(1H, d); 7.0 6.75 (1H, d); 5.82 (1H, m); 3.75 (1H, dd); 3.2 (1H, dd). MS(M+H): 341.

A suspension of(3R)-4,4,4-trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanethioamide(0.038 g, 0.00011 mol), chloroacetone (15 uL, 0.00019 mol) in ethanol (1mL, 0.02 mol) and 1,2-dichloroethane (1 mL, 0.01 mol) was heated toreflux overnight. Following this, the reaction mixture was filtered toremove insoluble material. The filtrate was dissolved in MeOH (1 mL) andDMF (1 mL) and purified by prep HPLC at pH10 to provide 6 mg of thepurified product as a colorless glass/oil, which was then trituratedwith MTBE/hexanes and was dried at 40° C. overnight to give 5.2 mg ofthe purified product as an off-white solid (13% yield).

¹H NMR (400 MHz, CDCl₃): δ 10.11 (1H, s); 8.88 (1H, s); 8.42 (1H, s);8.38 (1H, s); 7.45 (1H, d); 6.79 (1H, s); 6.65 (1H, d); 5.41 (1H, m);4.15 (1H, dd); 3.75 (H, dd); 2.18 (3H, s). MS (M+H): 379.

Example A: In Vitro JAK Kinase Assay

Compounds herein were tested for inhibitory activity of JAK targetsaccording to the following in vitro assay described in Park et al.,Analytical Biochemistry 1999, 269, 94-104. The catalytic domains ofhuman JAK1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a.781-1124) with an N-terminal His tag were expressed using baculovirus ininsect cells and purified. The catalytic activity of JAK1, JAK2 or JAK3was assayed by measuring the phosphorylation of a biotinylated peptide.The phosphorylated peptide was detected by homogenous time resolvedfluorescence (HTRF). IC₅₀s of compounds were measured for each kinase inthe reactions that contain the enzyme, ATP and 500 nM peptide in 50 mMTris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%)BSA. The ATP concentration in the reactions was 90 M for Jak1, 30 M forJak2 and 3 M for Jak3. Reactions were carried out at room temperaturefor 1 hr and then stopped with 20 L 45 mM EDTA, 300 nM SA-APC, 6 nMEu-Py20 in assay buffer (Perkin Elmer, Boston, Mass.). Binding to theEuropium labeled antibody took place for 40 minutes and HTRF signal wasmeasured on a Fusion plate reader (Perkin Elmer, Boston, Mass.).Compounds having an IC₅₀ of 10 M or less for any of the above-mentionedJAK targets were considered active.

Example B: Cellular Assays

One or more compounds herein were tested for inhibitory activity of JAKtargets according to at least one of the following cellular assays.

Cancer cell lines dependent on cytokines and hence JAK/STAT signaltransduction, for growth, were plated at 6000 cells per well (96 wellplate format) in RPMI 1640, 10% FBS, and 1 nG/mL of appropriatecytokine. Compounds were added to the cells in DMSO/media (finalconcentration 0.2% DMSO) and incubated for 72 hours at 37° C., 5% CO₂.The effect of compound on cell viability was assessed using theCellTiter-Glo Luminescent Cell Viability Assay (Promega) followed byTopCount (Perkin Elmer, Boston, Mass.) quantitation. Potentialoff-target effects of compounds were measured in parallel using anon-JAK driven cell line with the same assay readout. Compounds havingan IC₅₀ of 10 μM or less with selectivity for JAK driven proliferationwere considered active. All experiments were performed in duplicate.

The above cell lines can also be used to examine the effects ofcompounds on phosphorylation of JAK kinases or potential downstreamsubstrates such as STAT proteins, Akt, Shp2, or Erk. These experimentscan be performed following an overnight cytokine starvation, followed bya brief preincubation with compound (2 hours or less) and cytokinestimulation of approximately 1 hour or less. Proteins are then extractedfrom cells and analyzed by techniques familiar to those schooled in theart including Western blotting or ELISAs using antibodies that candifferentiate between phosphorylated and total protein. Theseexperiments can utilize normal or cancer cells to investigate theactivity of compounds on tumor cell survival biology or on mediators ofinflammatory disease. For example, with regards to the latter, cytokinessuch as IL-6, IL-12, IL-23, or IFN can be used to stimulate JAKactivation resulting in phosphorylation of STAT protein(s) andpotentially in transcriptional profiles (assessed by array or qPCRtechnology) or production and/or secretion of proteins, such as IL-17.The ability of compounds to inhibit these cytokine mediated effects canbe measured using techniques common to those schooled in the art.

Compounds herein can also be tested in cellular models designed toevaluate their potency and activity against mutant JAKs, for example,the JAK2V617F mutation found in myeloid proliferative disorders. Theseexperiments often utilize cytokine dependent cells of hematologicallineage (e.g. BaF/3) into which the wild-type or mutant JAK kinases areectopically expressed (James, C., et al. Nature 434:1144-1148; Staerk,J., et al. JBC 280:41893-41899). Endpoints include the effects ofcompounds on cell survival, proliferation, and phosphorylated JAK, STAT,Akt, or Erk proteins.

Certain compounds herein have been or can be evaluated for theiractivity inhibiting T-cell proliferation. Such as assay can beconsidered a second cytokine (i.e. JAK) driven proliferation assay andalso a simplistic assay of immune suppression or inhibition of immuneactivation. The following is a brief outline of how such experiments canbe performed. Peripheral blood mononuclear cells (PBMCs) are preparedfrom human whole blood samples using Ficoll Hypaque separation methodand T-cells (fraction 2000) can be obtained from PBMCs by elutriation.Freshly isolated human T-cells can be maintained in culture medium (RPMI1640 supplemented with 10% fetal bovine serum, 100 U/ml penicillin, 100μg/ml streptomycin) at a density of 2×10⁶ cells/ml at 37° C. for up to 2days. For IL-2 stimulated cell proliferation analysis, T-cells are firsttreated with Phytohemagglutinin (PHA) at a final concentration of 10μg/mL for 72 h. After washing once with PBS, 6000 cells/well are platedin 96-well plates and treated with compounds at different concentrationsin the culture medium in the presence of 100 U/mL human IL-2(ProSpec-Tany TechnoGene; Rehovot, Israel). The plates are incubated at37° C. for 72 h and the proliferation index is assessed usingCellTiter-Glo Luminescent reagents following the manufactory suggestedprotocol (Promega; Madison, Wis.).

Example C: In Vivo Anti-Tumor Efficacy

Compounds herein can be evaluated in human tumor xenograft models inimmune compromised mice. For example, a tumorigenic variant of the INA-6plasmacytoma cell line can be used to inoculate SCID mice subcutaneously(Burger, R., et al. Hematol J. 2:42-53, 2001). Tumor bearing animals canthen be randomized into drug or vehicle treatment groups and differentdoses of compounds can be administered by any number of the usual routesincluding oral, i.p., or continuous infusion using implantable pumps.Tumor growth is followed over time using calipers. Further, tumorsamples can be harvested at any time after the initiation of treatmentfor analysis as described above (Example B) to evaluate compound effectson JAK activity and downstream signaling pathways. In addition,selectivity of the compound(s) can be assessed using xenograft tumormodels that are driven by other know kinases (e.g. Bcr-Abl) such as theK562 tumor model.

Example D: Murine Skin Contact Delayed Hypersensitivity Response Test

Compounds herein can also be tested for their efficacies (of inhibitingJAK targets) in the T-cell driven murine delayed hypersensitivity testmodel. The murine skin contact delayed-type hypersensitivity (DTH)response is considered to be a valid model of clinical contactdermatitis, and other T-lymphocyte mediated immune disorders of theskin, such as psoriasis (Immunol Today. 1998 January; 19(1):37-44).Murine DTH shares multiple characteristics with psoriasis, including theimmune infiltrate, the accompanying increase in inflammatory cytokines,and keratinocyte hyperproliferation. Furthermore, many classes of agentsthat are efficacious in treating psoriasis in the clinic are alsoeffective inhibitors of the DTH response in mice (Agents Actions. 1993January; 38(1-2): 116-21).

On Day 0 and 1, Balb/c mice are sensitized with a topical application,to their shaved abdomen with the antigen 2,4,dinitro-fluorobenzene(DNFB). On day 5, ears are measured for thickness using an engineer'smicrometer. This measurement is recorded and used as a baseline. Both ofthe animals' ears are then challenged by a topical application of DNFBin a total of 20 μL (10 μL on the internal pinna and 10 μL on theexternal pinna) at a concentration of 0.2%. Twenty-four to seventy-twohours after the challenge, ears are measured again. Treatment with thetest compounds was given throughout the sensitization and challengephases (day −1 to day 7) or prior to and throughout the challenge phase(usually afternoon of day 4 to day 7). Treatment of the test compounds(in different concentration) was administered either systemically ortopically (topical application of the treatment to the ears). Efficaciesof the test compounds are indicated by a reduction in ear swellingcomparing to the situation without the treatment. Compounds causing areduction of 20% or more were considered efficacious. In someexperiments, the mice are challenged but not sensitized (negativecontrol).

The inhibitive effect (inhibiting activation of the JAK-STAT pathways)of the test compounds can be confirmed by immunohistochemical analysis.Activation of the JAK-STAT pathway(s) results in the formation andtranslocation of functional transcription factors. Further, the influxof immune cells and the increased proliferation of keratinocytes shouldalso provide unique expression profile changes in the ear that can beinvestigated and quantified. Formalin fixed and paraffin embedded earsections (harvested after the challenge phase in the DTH model) aresubjected to immunohistochemical analysis using an antibody thatspecifically interacts with phosphorylated STAT3 (clone 58E12, CellSignaling Technologies). The mouse ears are treated with test compounds,vehicle, or dexamethasone (a clinically efficacious treatment forpsoriasis), or without any treatment, in the DTH model for comparisons.Test compounds and the dexamethasone can produce similar transcriptionalchanges both qualitatively and quantitatively, and both the testcompounds and dexamethasone can reduce the number of infiltrating cells.Both systemically and topical administration of the test compounds canproduce inhibitive effects, i.e., reduction in the number ofinfiltrating cells and inhibition of the transcriptional changes.

Example E: In Vivo Anti-Inflammatory Activity

Compounds herein can be or have been evaluated in rodent or non-rodentmodels designed to replicate a single or complex inflammation response.For instance, rodent models of arthritis can be used to evaluate thetherapeutic potential of compounds dosed preventatively ortherapeutically. These models include but are not limited to mouse orrat collagen-induced arthritis, rat adjuvant-induced arthritis, andcollagen antibody-induced arthritis. Autoimmune diseases including, butnot limited to, multiple sclerosis, type I-diabetes mellitus,uveoretinitis, thyroditis, myasthenia gravis, immunoglobulinnephropathies, myocarditis, airway sensitization (asthma), lupus, orcolitis may also be used to evaluate the therapeutic potential ofcompounds herein. These models are well established in the researchcommunity and are familiar to those schooled in the art (CurrentProtocols in Immunology, Vol 3., Coligan, J. E. et al, Wiley Press.;Methods in Molecular Biology: Vol. 225, Inflammation Protocols.,Winyard, P. G. and Willoughby, D. A., Humana Press, 2003.).

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentapplication is incorporated herein by reference in its entirety.

1-88. (canceled)
 89. A method of treating an autoimmune skin disease ina patient in need thereof, comprising administering to the patient acompound, which is3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile,or a pharmaceutically acceptable salt thereof.
 90. The method of claim89, wherein the compound is(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile,or a pharmaceutically acceptable salt thereof.
 91. The method of claim90, wherein the compound or salt is administered as a pharmaceuticalcomposition comprising the compound or the salt and a pharmaceuticallyacceptable carrier.
 92. The method of claim 91, wherein thepharmaceutical composition is suitable for topical administration. 93.The method of claim 91, wherein the pharmaceutical composition issuitable for oral administration.
 94. The method of claim 91, whereinabout 5 to about 1000 mg of the compound, or pharmaceutically acceptablesalt thereof, is administered to the patient.
 95. The method of claim90, further comprising administering to the patient at least oneadditional therapeutic agent.
 96. The method of claim 95, wherein thetherapeutic agent is administered to a patient simultaneously orsequentially.
 97. The method of claim 95, wherein said therapeutic agentis an immunosuppressant.
 98. The method of claim 95, wherein saidtherapeutic agent is a steroid.
 99. The method of claim 95, wherein saidtherapeutic agent is a corticosteroid.
 100. The method of claim 99,wherein said corticosteroid is dexamethasone or prednisone.
 101. Themethod of claim 99, wherein said corticosteroid is dexamethasone. 102.The method of claim 99, wherein said corticosteroid is prednisone.